{"entity": "journal", "iuid": "47a2ca5b8d364a21adcf8f4009d27fe7", "timestamp": "2026-06-17T07:14:00.085Z", "links": {"self": {"href": "https://publications-affiliated.scilifelab.se/journal/J.%20Mol.%20Biol..json"}, "display": {"href": "https://publications-affiliated.scilifelab.se/journal/J.%20Mol.%20Biol."}}, "title": "J. Mol. Biol.", "issn": "1089-8638", "issn-l": "0022-2836", "publications_count": 19, "publications": [{"entity": "publication", "iuid": "e5695a0563f6415da2422587f4552e40", "links": {"self": {"href": "https://publications-affiliated.scilifelab.se/publication/e5695a0563f6415da2422587f4552e40.json"}, "display": {"href": "https://publications-affiliated.scilifelab.se/publication/e5695a0563f6415da2422587f4552e40"}}, "title": "Structure and Sequence-based Computational Approaches to Allosteric Signal Transduction: Application to Electromechanical Coupling in Voltage-gated Ion Channels.", "authors": [{"family": "Elbahnsi", "given": "Ahmad", "initials": "A"}, {"family": "Delemotte", "given": "Lucie", "initials": "L"}], "type": "journal article", "published": "2021-08-20", "journal": {"title": "J. Mol. Biol.", "issn": "1089-8638", "volume": "433", "issue": "17", "pages": "167095", "issn-l": "0022-2836"}, "abstract": "Allosteric signaling underlies the function of many biomolecules, including membrane proteins such as ion channels. Experimental methods have enabled specific quantitative insights into the coupling between the voltage sensing domain (VSD) and the pore gate of voltage-gated ion channels, located tens of \u00c5ngstr\u00f6m apart from one another, as well as pinpointed specific residues and domains that participate in electromechanical signal transmission. Nevertheless, an overall atomic-level resolution picture is difficult to obtain from these methods alone. Today, thanks to the cryo-EM resolution revolution, we have access to high resolution structures of many different voltage-gated ion channels in various conformational states, putting a quantitative description of the processes at the basis of these changes within our close reach. Here, we review computational methods that build on structures to detect and characterize allosteric signaling and pathways. We then examine what has been learned so far about electromechanical coupling between VSD and pore using such methods. While no general theory of electromechanical coupling in voltage-gated ion channels integrating results from all these methods is available yet, we outline the types of insights that could be achieved in the near future using the methods that have not yet been put to use in this field of application.", "doi": "10.1016/j.jmb.2021.167095", "pmid": "34107281", "labels": {"Lucie Delemotte": null, "SciLifeLab Fellow": null}, "xrefs": [{"db": "pii", "key": "S0022-2836(21)00319-3"}], "notes": [], "created": "2021-12-08T08:10:08.875Z", "modified": "2022-11-04T11:32:12.647Z"}, {"entity": "publication", "iuid": "b271601618d74dea989e0ec2cc2f1279", "links": {"self": {"href": "https://publications-affiliated.scilifelab.se/publication/b271601618d74dea989e0ec2cc2f1279.json"}, "display": {"href": "https://publications-affiliated.scilifelab.se/publication/b271601618d74dea989e0ec2cc2f1279"}}, "title": "Influenza Hemifusion Phenotype Depends on Membrane Context: Differences in Cell-Cell and Virus-Cell Fusion.", "authors": [{"family": "Zawada", "given": "Katarzyna E", "initials": "KE"}, {"family": "Okamoto", "given": "Kenta", "initials": "K"}, {"family": "Kasson", "given": "Peter M", "initials": "PM"}], "type": "journal article", "published": "2018-03-02", "journal": {"title": "J. Mol. Biol.", "issn": "1089-8638", "volume": "430", "issue": "5", "pages": "594-601", "issn-l": "0022-2836"}, "abstract": "Influenza viral entry into the host cell cytoplasm is accomplished by a process of membrane fusion mediated by the viral hemagglutinin protein. Hemagglutinin acts in a pH-triggered fashion, inserting a short fusion peptide into the host membrane followed by refolding of a coiled-coil structure to draw the viral envelope and host membranes together. Mutations to this fusion peptide provide an important window into viral fusion mechanisms and protein-membrane interactions. Here, we show that a well-described fusion peptide mutant, G1S, has a phenotype that depends strongly on the viral membrane context. The G1S mutant is well known to cause a \"hemifusion\" phenotype based on experiments in transfected cells, where cells expressing G1S hemagglutinin can undergo lipid mixing in a pH-triggered fashion similar to virus but will not support fusion pores. We compare fusion by the G1S hemagglutinin mutant expressed either in cells or in influenza virions and show that this hemifusion phenotype occurs in transfected cells but that native virions are able to support full fusion, albeit at a slower rate and 10-100\u00d7 reduced infectious titer. We explain this with a quantitative model where the G1S mutant, instead of causing an absolute block of fusion, alters the protein stoichiometry required for fusion. This change slightly slows fusion at high hemagglutinin density, as on the viral surface, but at lower hemagglutinin density produces a hemifusion phenotype. The quantitative model thus reproduces the observed virus-cell and cell-cell fusion phenotypes, yielding a unified explanation where membrane context can control the observed viral fusion phenotype.", "doi": "10.1016/j.jmb.2018.01.006", "pmid": "29355500", "labels": {"Affiliated researcher": null}, "xrefs": [{"db": "pii", "key": "S0022-2836(18)30009-3"}, {"db": "pmc", "key": "PMC5831491"}, {"db": "mid", "key": "NIHMS935057"}], "notes": [], "created": "2018-12-05T12:43:55.853Z", "modified": "2018-12-05T12:43:55.872Z"}, {"entity": "publication", "iuid": "8b433289b86049939eab3c1a323f3661", "links": {"self": {"href": "https://publications-affiliated.scilifelab.se/publication/8b433289b86049939eab3c1a323f3661.json"}, "display": {"href": "https://publications-affiliated.scilifelab.se/publication/8b433289b86049939eab3c1a323f3661"}}, "title": "Mechanism of Peptide Binding and Cleavage by the Human Mitochondrial Peptidase Neurolysin.", "authors": [{"family": "Teixeira", "given": "Pedro F", "initials": "PF"}, {"family": "Masuyer", "given": "Geoffrey", "initials": "G"}, {"family": "Pinho", "given": "Catarina M", "initials": "CM"}, {"family": "Branca", "given": "Rui M M", "initials": "RMM"}, {"family": "Kmiec", "given": "Beata", "initials": "B"}, {"family": "Wallin", "given": "Cecilia", "initials": "C"}, {"family": "W\u00e4rml\u00e4nder", "given": "Sebastian K T S", "initials": "SKTS"}, {"family": "Berntsson", "given": "Ronnie P-A", "initials": "RP"}, {"family": "Ankarcrona", "given": "Maria", "initials": "M"}, {"family": "Gr\u00e4slund", "given": "Astrid", "initials": "A"}, {"family": "Lehti\u00f6", "given": "Janne", "initials": "J"}, {"family": "Stenmark", "given": "P\u00e5l", "initials": "P"}, {"family": "Glaser", "given": "Elzbieta", "initials": "E"}], "type": "journal article", "published": "2018-02-02", "journal": {"title": "J. Mol. Biol.", "issn": "1089-8638", "volume": "430", "issue": "3", "pages": "348-362", "issn-l": "0022-2836"}, "abstract": "Proteolysis plays an important role in mitochondrial biogenesis, from the processing of newly imported precursor proteins to the degradation of mitochondrial targeting peptides. Disruption of peptide degradation activity in yeast, plant and mammalian mitochondria is known to have deleterious consequences for organism physiology, highlighting the important role of mitochondrial peptidases. In the present work, we show that the human mitochondrial peptidase neurolysin (hNLN) can degrade mitochondrial presequence peptides as well as other fragments up to 19 amino acids long. The crystal structure of hNLN", "doi": "10.1016/j.jmb.2017.11.011", "pmid": "29183787", "labels": {"Affiliated researcher": null}, "xrefs": [{"db": "pii", "key": "S0022-2836(17)30561-2"}], "notes": [], "created": "2018-12-05T12:48:17.822Z", "modified": "2018-12-05T12:48:17.840Z"}, {"entity": "publication", "iuid": "94180fc270c1425fb4e3ddeacce0f4b6", "links": {"self": {"href": "https://publications-affiliated.scilifelab.se/publication/94180fc270c1425fb4e3ddeacce0f4b6.json"}, "display": {"href": "https://publications-affiliated.scilifelab.se/publication/94180fc270c1425fb4e3ddeacce0f4b6"}}, "title": "Consequences of Epithelial Inflammasome Activation by Bacterial Pathogens.", "authors": [{"family": "Sellin", "given": "Mikael E", "initials": "ME"}, {"family": "M\u00fcller", "given": "Anna A", "initials": "AA"}, {"family": "Hardt", "given": "Wolf-Dietrich", "initials": "WD"}], "type": "journal article", "published": "2018-01-19", "journal": {"title": "J. Mol. Biol.", "issn": "1089-8638", "issn-l": "0022-2836", "volume": "430", "issue": "2", "pages": "193-206"}, "abstract": "Inflammasome signaling impinges on the activation of inflammatory caspases (i.e., caspase-1 and caspase-4/5/11) and endows host cells with a sentinel system to sense microbial intrusion and thereby initiate appropriate immune responses. Lately, it has become evident that mammalian inflammasome-dependent responses to infection are not confined solely to cells of hematopoietic origin. Epithelial cells that line the body's mucosal surfaces use inflammasome signaling to sense and counteract pathogenic microorganisms that compromise barrier integrity. Many of the molecular mechanisms of epithelial inflammasome signaling remain unexplored. However, it now seems clear that epithelial inflammasome activation has a profound impact both on the infected cell itself and on its ability to communicate with other cell types of the mucosa. Here, we summarize current knowledge regarding the output of epithelial inflammasome activation during bacterial infection. Well-established downstream effects include epithelial cell death, release of soluble mediators, and subsequent recruitment of effector cell types, including NK cells, mast cells, and neutrophils, to sites of mucosal infection. We discuss the implications of recent findings for antibacterial defense in the mucosa and sketch out areas for future exploration.", "doi": "10.1016/j.jmb.2017.03.031", "pmid": "28454742", "labels": {"Affiliated researcher": null, "Mikael Sellin": null, "SciLifeLab Fellow": null}, "xrefs": [{"db": "pii", "key": "S0022-2836(17)30183-3"}], "notes": [], "created": "2018-12-03T14:44:32.186Z", "modified": "2022-11-04T11:32:18.049Z"}, {"entity": "publication", "iuid": "f59b196e6cc84465868a47d2b54b44ef", "links": {"self": {"href": "https://publications-affiliated.scilifelab.se/publication/f59b196e6cc84465868a47d2b54b44ef.json"}, "display": {"href": "https://publications-affiliated.scilifelab.se/publication/f59b196e6cc84465868a47d2b54b44ef"}}, "title": "Trap", "authors": [{"family": "Mayor-Ruiz", "given": "Cristina", "initials": "C"}, {"family": "Dominguez", "given": "Orlando", "initials": "O"}, {"family": "Fernandez-Capetillo", "given": "Oscar", "initials": "O"}], "type": "journal article", "published": "2017-09-01", "journal": {"title": "J. Mol. Biol.", "issn": "1089-8638", "volume": "429", "issue": "18", "pages": "2780-2789", "issn-l": "0022-2836"}, "abstract": "The development of haploid mammalian cell lines, coupled to next-generation sequencing, has recently facilitated forward genetic screenings in mammals. For mutagenesis, retrovirus- or transposon-based gene traps are frequently used. Current methods to map gene-trap insertions are based on inverse or splinkerette PCR, which despite their efficacy are prone to artifacts and do not provide information on expression of the targeted gene. Here, we describe a new RNA sequencing-based method (Trap", "doi": "10.1016/j.jmb.2017.07.020", "pmid": "28782559", "labels": {"Affiliated researcher": null}, "xrefs": [{"db": "pii", "key": "S0022-2836(17)30370-4"}, {"db": "pmc", "key": "PMC5695663"}, {"db": "mid", "key": "EMS74344"}], "notes": [], "created": "2018-12-05T12:27:36.063Z", "modified": "2018-12-05T12:27:36.082Z"}, {"entity": "publication", "iuid": "f314641a4ee34457948ac8fa8b504cae", "links": {"self": {"href": "https://publications-affiliated.scilifelab.se/publication/f314641a4ee34457948ac8fa8b504cae.json"}, "display": {"href": "https://publications-affiliated.scilifelab.se/publication/f314641a4ee34457948ac8fa8b504cae"}}, "title": "A Fluorophore Fusion Construct of Human Profilin I with Non-Compromised Poly(L-Proline) Binding Capacity Suitable for Imaging.", "authors": [{"family": "Nejedla", "given": "Michaela", "initials": "M"}, {"family": "Li", "given": "Zhilun", "initials": "Z"}, {"family": "Masser", "given": "Anna E", "initials": "AE"}, {"family": "Biancospino", "given": "Matteo", "initials": "M"}, {"family": "Spiess", "given": "Matthias", "initials": "M"}, {"family": "Mackowiak", "given": "Sebastian D", "initials": "SD"}, {"family": "Friedl\u00e4nder", "given": "Marc R", "initials": "MR"}, {"family": "Karlsson", "given": "Roger", "initials": "R"}], "type": "journal article", "published": "2017-04-07", "journal": {"title": "J. Mol. Biol.", "issn": "1089-8638", "issn-l": "0022-2836", "volume": "429", "issue": "7", "pages": "964-976"}, "abstract": "Profilin is vital for actin organisation in eukaryotic cells. It controls actin filament formation by binding monomeric actin and numerous proteins involved in polarised actin assembly. Important for the latter is the interaction surface formed by the N- and C-terminal helices, which pack close to each other on one side of the molecule at a distance from the actin site and mediate binding to poly-proline sequences present in many of the targeted proteins. Via these interactions, profilin contributes to the spatiotemporal control of actin filament growth. Studies of profilin dynamics in living cells by imaging techniques have been hampered by problems to generate fusion constructs with fluorophore proteins without negatively impacting on its poly-proline binding. With the object to circumvent this problem, we have generated an internal fusion of profilin with the green fluorescent variant citrine, here referred to as citrine-profilin. The characterisation of citrine-profilin (CIT-Pfn) demonstrates that it has full capacity to interact with poly-proline and also binds phosphatidylinositol lipids and actin, albeit with 10 times reduced affinity for the latter. Imaging of living cells expressing CIT-Pfn showed a distribution of the fusion protein similar to endogenous profilin. Furthermore, CIT-Pfn rescued the phenotypes observed after the Crispr/Cas9 knockout of the profilin 1 gene, including the lost migratory capacity characterising the knockout cells. Based on this, we conclude that the CIT-Pfn construct will be useful as a tool for displaying profilin localisation in living cells and obtaining information on its dynamic organisation under different conditions and activations of the actin microfilament and microtubule systems.", "doi": "10.1016/j.jmb.2017.01.004", "pmid": "28077285", "labels": {"Affiliated researcher": null, "Marc Friedl\u00e4nder": null, "SciLifeLab Fellow": null}, "xrefs": [{"db": "pii", "key": "S0022-2836(17)30018-9"}], "notes": [], "created": "2018-12-03T14:42:55.882Z", "modified": "2022-11-04T11:32:18.825Z"}, {"entity": "publication", "iuid": "09e725994a044221a7d35d4212082903", "links": {"self": {"href": "https://publications-affiliated.scilifelab.se/publication/09e725994a044221a7d35d4212082903.json"}, "display": {"href": "https://publications-affiliated.scilifelab.se/publication/09e725994a044221a7d35d4212082903"}}, "title": "Trigger Factor Reduces the Force Exerted on the Nascent Chain by a Cotranslationally Folding Protein.", "authors": [{"family": "Nilsson", "given": "Ola B", "initials": "OB"}, {"family": "M\u00fcller-Lucks", "given": "Annika", "initials": "A"}, {"family": "Kramer", "given": "G\u00fcnter", "initials": "G"}, {"family": "Bukau", "given": "Bernd", "initials": "B"}, {"family": "von Heijne", "given": "Gunnar", "initials": "G"}], "type": "journal article", "published": "2016-03-27", "journal": {"title": "J. Mol. Biol.", "issn": "1089-8638", "volume": "428", "issue": "6", "pages": "1356-1364", "issn-l": "0022-2836"}, "abstract": "Cotranslational protein folding can generate pulling forces on the nascent chain that can affect the instantaneous translation rate and thereby possibly feed back on the folding process. Such feedback would represent a new way of coupling translation and folding, different from coupling based on, for example, codon usage. However, to date, we have carried out the experiments used to measure pulling forces generated by cotranslational protein folding either in reconstituted in vitro translation systems lacking chaperones, in ill-defined cell lysates, or in vivo; hence, the effects of chaperones on force generation by folding are unknown. Here, we have studied the cotranslational folding of dihydrofolate reductase (DHFR) in the absence and in the presence of the chaperones trigger factor (TF) and GroEL/ES. DHFR was tethered to the ribosome via a C-terminal linker of varying length, ending with the SecM translational arrest peptide that serves as an intrinsic force sensor reporting on the force generated on the nascent chain when DHFR folds. We find that DHFR folds into its native structure only when it has emerged fully outside the ribosome and that TF and GroEL alone substantially reduces the force generated on the nascent chain by the folding of DHFR, while GroEL/ES has no effect. TF therefore weakens the possible coupling between cotranslational folding and translation.", "doi": "10.1016/j.jmb.2016.02.014", "pmid": "26906929", "labels": {"Affiliated researcher": null}, "xrefs": [{"db": "pii", "key": "S0022-2836(16)00130-3"}], "notes": [], "created": "2018-12-05T09:48:31.504Z", "modified": "2018-12-05T09:48:31.524Z"}, {"entity": "publication", "iuid": "bbcce59fd1314647a64b9202f531138d", "links": {"self": {"href": "https://publications-affiliated.scilifelab.se/publication/bbcce59fd1314647a64b9202f531138d.json"}, "display": {"href": "https://publications-affiliated.scilifelab.se/publication/bbcce59fd1314647a64b9202f531138d"}}, "title": "Crosstalk between Hippo and TGF\u03b2: Subcellular Localization of YAP/TAZ/Smad Complexes.", "authors": [{"family": "Grannas", "given": "Karin", "initials": "K"}, {"family": "Arng\u00e5rden", "given": "Linda", "initials": "L"}, {"family": "L\u00f6nn", "given": "Peter", "initials": "P"}, {"family": "Mazurkiewicz", "given": "Magdalena", "initials": "M"}, {"family": "Blokzijl", "given": "Andries", "initials": "A"}, {"family": "Zieba", "given": "Agata", "initials": "A"}, {"family": "S\u00f6derberg", "given": "Ola", "initials": "O"}], "type": "journal article", "published": "2015-10-23", "journal": {"title": "J. Mol. Biol.", "issn": "1089-8638", "volume": "427", "issue": "21", "pages": "3407-3415", "issn-l": "0022-2836"}, "abstract": "The Hippo pathway plays a crucial role in growth control, proliferation and tumor suppression. Activity of the signaling pathway is associated with cell density sensing and tissue organization. Furthermore, the Hippo pathway helps to coordinate cellular processes through crosstalk with growth-factor-mediated signaling pathways such as TGF\u03b2. Here we have examined the localization of interactions between proteins of the Hippo pathway (YAP/TAZ) and TGF\u03b2 (Smad2/3) signaling pathway by using in situ proximity ligation assays. We investigated the formation of protein complexes between YAP/TAZ and Smad2/3 and examined how these interactions were affected by TGF\u03b2 stimulation and cell density in HaCaT keratinocytes and in Smad4-deficient HT29 colon cancer cells. We demonstrate that TGF\u03b2 induces formation of YAP/TAZ-Smad2/3 complexes in HaCaT cells. Under sparse cell conditions, the complexes were detected to a higher degree and were predominantly located in the nucleus, while under dense culture conditions, the complexes were fewer and mainly located in the cytoplasm. Surprisingly, we could not detect any YAP/TAZ-Smad2/3 complexes in HT29 cells. To examine if Smad4 deficiency was responsible for the absence of interactions, we treated HaCaT cells with siRNA targeting Smad4. However, we could still observe complex formation in the siRNA-treated cells, suggesting that Smad4 is not essential for the YAP-Smad2/3 interaction. In conclusion, this study shows localized, density-dependent formation of YAP/TAZ-Smad2/3 complexes in HaCaT cells and provides evidence supporting a crosstalk between the Hippo and the TGF\u03b2 signaling pathways. ", "doi": "10.1016/j.jmb.2015.04.015", "pmid": "25937570", "labels": {"Affiliated researcher": null}, "xrefs": [{"db": "pii", "key": "S0022-2836(15)00269-7"}], "notes": [], "created": "2018-12-05T09:17:07.176Z", "modified": "2018-12-05T09:17:07.195Z"}, {"entity": "publication", "iuid": "9b15392153fa4502be80b5beea9cba56", "links": {"self": {"href": "https://publications-affiliated.scilifelab.se/publication/9b15392153fa4502be80b5beea9cba56.json"}, "display": {"href": "https://publications-affiliated.scilifelab.se/publication/9b15392153fa4502be80b5beea9cba56"}}, "title": "Next-generation pathology--surveillance of tumor microecology.", "authors": [{"family": "Koos", "given": "Bj\u00f6rn", "initials": "B"}, {"family": "Kamali-Moghaddam", "given": "Masood", "initials": "M"}, {"family": "David", "given": "Leonor", "initials": "L"}, {"family": "Sobrinho-Sim\u00f5es", "given": "Manuel", "initials": "M"}, {"family": "Dimberg", "given": "Anna", "initials": "A"}, {"family": "Nilsson", "given": "Mats", "initials": "M"}, {"family": "W\u00e4hlby", "given": "Carolina", "initials": "C"}, {"family": "S\u00f6derberg", "given": "Ola", "initials": "O"}], "type": "journal article", "published": "2015-06-05", "journal": {"title": "J. Mol. Biol.", "issn": "1089-8638", "volume": "427", "issue": "11", "pages": "2013-2022", "issn-l": "0022-2836"}, "abstract": "A tumor is a heterogeneous population of cells that provides an environment in which every cell resides in a microenvironmental niche. Microscopic evaluation of tissue sections, based on histology and immunohistochemistry, has been a cornerstone in pathology for decades. However, the dawn of novel technologies to investigate genetic aberrations is currently adopted in routine molecular pathology. We herein describe our view on how recent developments in molecular technologies, focusing on proximity ligation assay and padlock probes, can be applied to merge the two branches of pathology, allowing molecular profiling under histologic observation. We also discuss how the use of image analysis will be pivotal to obtain information at a cellular level and to interpret holistic images of tissue sections. By understanding the cellular communications in the microecology of tumors, we will be at a better position to predict disease progression and response to therapy. ", "doi": "10.1016/j.jmb.2015.02.017", "pmid": "25725260", "labels": {"Affiliated researcher": null}, "xrefs": [{"db": "pii", "key": "S0022-2836(15)00111-4"}], "notes": [], "created": "2018-12-05T11:31:27.680Z", "modified": "2018-12-05T11:31:27.698Z"}, {"entity": "publication", "iuid": "43d0b351e6554133ae3e8f892983c5a8", "links": {"self": {"href": "https://publications-affiliated.scilifelab.se/publication/43d0b351e6554133ae3e8f892983c5a8.json"}, "display": {"href": "https://publications-affiliated.scilifelab.se/publication/43d0b351e6554133ae3e8f892983c5a8"}}, "title": "Catalytic stimulation by restrained active-site floppiness--the case of high density lipoprotein-bound serum paraoxonase-1.", "authors": [{"family": "Ben-David", "given": "Moshe", "initials": "M"}, {"family": "Sussman", "given": "Joel L", "initials": "JL"}, {"family": "Maxwell", "given": "Christopher I", "initials": "CI"}, {"family": "Szeler", "given": "Klaudia", "initials": "K"}, {"family": "Kamerlin", "given": "Shina C L", "initials": "SCL"}, {"family": "Tawfik", "given": "Dan S", "initials": "DS"}], "type": "comparative study", "published": "2015-03-27", "journal": {"title": "J. Mol. Biol.", "issn": "1089-8638", "volume": "427", "issue": "6 Pt B", "pages": "1359-1374", "issn-l": "0022-2836"}, "abstract": "Despite the abundance of membrane-associated enzymes, the mechanism by which membrane binding stabilizes these enzymes and stimulates their catalysis remains largely unknown. Serum paraoxonase-1 (PON1) is a lipophilic lactonase whose stability and enzymatic activity are dramatically stimulated when associated with high-density lipoprotein (HDL) particles. Our mutational and structural analyses, combined with empirical valence bond simulations, reveal a network of hydrogen bonds that connect HDL binding residues with Asn168--a key catalytic residue residing >15\u00c5 from the HDL contacting interface. This network ensures precise alignment of N168, which, in turn, ligates PON1's catalytic calcium and aligns the lactone substrate for catalysis. HDL binding restrains the overall motion of the active site and particularly of N168, thus reducing the catalytic activation energy barrier. We demonstrate herein that disturbance of this network, even at its most far-reaching periphery, undermines PON1's activity. Membrane binding thus immobilizes long-range interactions via second- and third-shell residues that reduce the active site's floppiness and pre-organize the catalytic residues. Although this network is critical for efficient catalysis, as demonstrated here, unraveling these long-rage interaction networks is challenging, let alone their implementation in artificial enzyme design.", "doi": "10.1016/j.jmb.2015.01.013", "pmid": "25644661", "labels": {"Affiliated researcher": null}, "xrefs": [{"db": "pii", "key": "S0022-2836(15)00035-2"}, {"db": "PDB", "key": "4Q1U"}], "notes": [], "created": "2018-12-05T09:31:11.306Z", "modified": "2018-12-05T09:31:11.327Z"}, {"entity": "publication", "iuid": "a97cedff85234a89bd78289d3a9544c8", "links": {"self": {"href": "https://publications-affiliated.scilifelab.se/publication/a97cedff85234a89bd78289d3a9544c8.json"}, "display": {"href": "https://publications-affiliated.scilifelab.se/publication/a97cedff85234a89bd78289d3a9544c8"}}, "title": "The code for directing proteins for translocation across ER membrane: SRP cotranslationally recognizes specific features of a signal sequence.", "authors": [{"family": "Nilsson", "given": "IngMarie", "initials": "I"}, {"family": "Lara", "given": "Patricia", "initials": "P"}, {"family": "Hessa", "given": "Tara", "initials": "T"}, {"family": "Johnson", "given": "Arthur E", "initials": "AE"}, {"family": "von Heijne", "given": "Gunnar", "initials": "G"}, {"family": "Karamyshev", "given": "Andrey L", "initials": "AL"}], "type": "journal article", "published": "2015-03-27", "journal": {"title": "J. Mol. Biol.", "issn": "1089-8638", "volume": "427", "issue": "6 Pt A", "pages": "1191-1201", "issn-l": "0022-2836"}, "abstract": "The signal recognition particle (SRP) cotranslationally recognizes signal sequences of secretory proteins and targets ribosome-nascent chain complexes to the SRP receptor in the endoplasmic reticulum membrane, initiating translocation of the nascent chain through the Sec61 translocon. Although signal sequences do not have homology, they have similar structural regions: a positively charged N-terminus, a hydrophobic core and a more polar C-terminal region that contains the cleavage site for the signal peptidase. Here, we have used site-specific photocrosslinking to study SRP-signal sequence interactions. A photoreactive probe was incorporated into the middle of wild-type or mutated signal sequences of the secretory protein preprolactin by in vitro translation of mRNAs containing an amber-stop codon in the signal peptide in the presence of the N(\u03b5)-(5-azido-2 nitrobenzoyl)-Lys-tRNA(amb) amber suppressor. A homogeneous population of SRP-ribosome-nascent chain complexes was obtained by the use of truncated mRNAs in translations performed in the presence of purified canine SRP. Quantitative analysis of the photoadducts revealed that charged residues at the N-terminus of the signal sequence or in the early part of the mature protein have only a mild effect on the SRP-signal sequence association. However, deletions of amino acid residues in the hydrophobic portion of the signal sequence severely affect SRP binding. The photocrosslinking data correlate with targeting efficiency and translocation across the membrane. Thus, the hydrophobic core of the signal sequence is primarily responsible for its recognition and binding by SRP, while positive charges fine-tune the SRP-signal sequence affinity and targeting to the translocon. ", "doi": "10.1016/j.jmb.2014.06.014", "pmid": "24979680", "labels": {"Affiliated researcher": null}, "xrefs": [{"db": "pii", "key": "S0022-2836(14)00307-6"}, {"db": "pmc", "key": "PMC4277940"}, {"db": "mid", "key": "NIHMS613012"}], "notes": [], "created": "2018-12-05T10:19:13.849Z", "modified": "2018-12-05T10:19:13.868Z"}, {"entity": "publication", "iuid": "6f969a016e9648b8be29e7ae97c7bb07", "links": {"self": {"href": "https://publications-affiliated.scilifelab.se/publication/6f969a016e9648b8be29e7ae97c7bb07.json"}, "display": {"href": "https://publications-affiliated.scilifelab.se/publication/6f969a016e9648b8be29e7ae97c7bb07"}}, "title": "Mechanisms of integral membrane protein insertion and folding.", "authors": [{"family": "Cymer", "given": "Florian", "initials": "F"}, {"family": "von Heijne", "given": "Gunnar", "initials": "G"}, {"family": "White", "given": "Stephen H", "initials": "SH"}], "type": "journal article", "published": "2015-03-13", "journal": {"title": "J. Mol. Biol.", "issn": "1089-8638", "volume": "427", "issue": "5", "pages": "999-1022", "issn-l": "0022-2836"}, "abstract": "The biogenesis, folding, and structure of \u03b1-helical membrane proteins (MPs) are important to understand because they underlie virtually all physiological processes in cells including key metabolic pathways, such as the respiratory chain and the photosystems, as well as the transport of solutes and signals across membranes. Nearly all MPs require translocons--often referred to as protein-conducting channels--for proper insertion into their target membrane. Remarkable progress toward understanding the structure and functioning of translocons has been made during the past decade. Here, we review and assess this progress critically. All available evidence indicates that MPs are equilibrium structures that achieve their final structural states by folding along thermodynamically controlled pathways. The main challenge for cells is the targeting and membrane insertion of highly hydrophobic amino acid sequences. Targeting and insertion are managed in cells principally by interactions between ribosomes and membrane-embedded translocons. Our review examines the biophysical and biological boundaries of MP insertion and the folding of polytopic MPs in vivo. A theme of the review is the under-appreciated role of basic thermodynamic principles in MP folding and assembly. Thermodynamics not only dictates the final folded structure but also is the driving force for the evolution of the ribosome-translocon system of assembly. We conclude the review with a perspective suggesting a new view of translocon-guided MP insertion.", "doi": "10.1016/j.jmb.2014.09.014", "pmid": "25277655", "labels": {"Affiliated researcher": null}, "xrefs": [{"db": "pmc", "key": "PMC4339636"}, {"db": "mid", "key": "NIHMS632795"}, {"db": "pii", "key": "S0022-2836(14)00513-0"}], "notes": [], "created": "2018-12-05T08:37:01.356Z", "modified": "2018-12-05T08:37:01.388Z"}, {"entity": "publication", "iuid": "eed507c235ba47618faac528588486c5", "links": {"self": {"href": "https://publications-affiliated.scilifelab.se/publication/eed507c235ba47618faac528588486c5.json"}, "display": {"href": "https://publications-affiliated.scilifelab.se/publication/eed507c235ba47618faac528588486c5"}}, "title": "The positive inside rule is stronger when followed by a transmembrane helix.", "authors": [{"family": "Virkki", "given": "Minttu T", "initials": "MT"}, {"family": "Peters", "given": "Christoph", "initials": "C"}, {"family": "Nilsson", "given": "Daniel", "initials": "D"}, {"family": "S\u00f6rensen", "given": "Therese", "initials": "T"}, {"family": "Cristobal", "given": "Susana", "initials": "S"}, {"family": "Wallner", "given": "Bj\u00f6rn", "initials": "B"}, {"family": "Elofsson", "given": "Arne", "initials": "A"}], "type": "journal article", "published": "2014-08-12", "journal": {"title": "J. Mol. Biol.", "issn": "1089-8638", "volume": "426", "issue": "16", "pages": "2982-2991", "issn-l": "0022-2836"}, "abstract": "The translocon recognizes transmembrane helices with sufficient level of hydrophobicity and inserts them into the membrane. However, sometimes less hydrophobic helices are also recognized. Positive inside rule, orientational preferences of and specific interactions with neighboring helices have been shown to aid in the recognition of these helices, at least in artificial systems. To better understand how the translocon inserts marginally hydrophobic helices, we studied three naturally occurring marginally hydrophobic helices, which were previously shown to require the subsequent helix for efficient translocon recognition. We find no evidence for specific interactions when we scan all residues in the subsequent helices. Instead, we identify arginines located at the N-terminal part of the subsequent helices that are crucial for the recognition of the marginally hydrophobic transmembrane helices, indicating that the positive inside rule is important. However, in two of the constructs, these arginines do not aid in the recognition without the rest of the subsequent helix; that is, the positive inside rule alone is not sufficient. Instead, the improved recognition of marginally hydrophobic helices can here be explained as follows: the positive inside rule provides an orientational preference of the subsequent helix, which in turn allows the marginally hydrophobic helix to be inserted; that is, the effect of the positive inside rule is stronger if positively charged residues are followed by a transmembrane helix. Such a mechanism obviously cannot aid C-terminal helices, and consequently, we find that the terminal helices in multi-spanning membrane proteins are more hydrophobic than internal helices. ", "doi": "10.1016/j.jmb.2014.06.002", "pmid": "24927974", "labels": {"Affiliated researcher": null}, "xrefs": [{"db": "pii", "key": "S0022-2836(14)00281-2"}], "notes": [], "created": "2018-12-05T11:32:43.198Z", "modified": "2018-12-05T11:32:43.218Z"}, {"entity": "publication", "iuid": "08a2ea0bfa4445b5b7d7b53a73c62e9e", "links": {"self": {"href": "https://publications-affiliated.scilifelab.se/publication/08a2ea0bfa4445b5b7d7b53a73c62e9e.json"}, "display": {"href": "https://publications-affiliated.scilifelab.se/publication/08a2ea0bfa4445b5b7d7b53a73c62e9e"}}, "title": "Large tilts in transmembrane helices can be induced during tertiary structure formation.", "authors": [{"family": "Virkki", "given": "Minttu", "initials": "M"}, {"family": "Boekel", "given": "Carolina", "initials": "C"}, {"family": "Illerg\u00e5rd", "given": "Kristoffer", "initials": "K"}, {"family": "Peters", "given": "Christoph", "initials": "C"}, {"family": "Shu", "given": "Nanjiang", "initials": "N"}, {"family": "Tsirigos", "given": "Konstantinos D", "initials": "KD"}, {"family": "Elofsson", "given": "Arne", "initials": "A"}, {"family": "von Heijne", "given": "Gunnar", "initials": "G"}, {"family": "Nilsson", "given": "IngMarie", "initials": "I"}], "type": "journal article", "published": "2014-06-26", "journal": {"title": "J. Mol. Biol.", "issn": "1089-8638", "volume": "426", "issue": "13", "pages": "2529-2538", "issn-l": "0022-2836"}, "abstract": "While early structural models of helix-bundle integral membrane proteins posited that the transmembrane \u03b1-helices [transmembrane helices (TMHs)] were orientated more or less perpendicular to the membrane plane, there is now ample evidence from high-resolution structures that many TMHs have significant tilt angles relative to the membrane. Here, we address the question whether the tilt is an intrinsic property of the TMH in question or if it is imparted on the TMH during folding of the protein. Using a glycosylation mapping technique, we show that four highly tilted helices found in multi-spanning membrane proteins all have much shorter membrane-embedded segments when inserted by themselves into the membrane than seen in the high-resolution structures. This suggests that tilting can be induced by tertiary packing interactions within the protein, subsequent to the initial membrane-insertion step. ", "doi": "10.1016/j.jmb.2014.04.020", "pmid": "24793448", "labels": {"Affiliated researcher": null}, "xrefs": [{"db": "pii", "key": "S0022-2836(14)00204-6"}], "notes": [], "created": "2018-12-05T11:53:30.968Z", "modified": "2018-12-05T11:53:30.987Z"}, {"entity": "publication", "iuid": "8232222e52824858861fa2e7050e65ed", "links": {"self": {"href": "https://publications-affiliated.scilifelab.se/publication/8232222e52824858861fa2e7050e65ed.json"}, "display": {"href": "https://publications-affiliated.scilifelab.se/publication/8232222e52824858861fa2e7050e65ed"}}, "title": "Why have small multidrug resistance proteins not evolved into fused, internally duplicated structures?", "authors": [{"family": "Lloris-Garcer\u00e1", "given": "Pilar", "initials": "P"}, {"family": "Sepp\u00e4l\u00e4", "given": "Susanna", "initials": "S"}, {"family": "Slusky", "given": "Joanna S G", "initials": "JS"}, {"family": "Rapp", "given": "Mikaela", "initials": "M"}, {"family": "von Heijne", "given": "Gunnar", "initials": "G"}], "type": "journal article", "published": "2014-05-29", "journal": {"title": "J. Mol. Biol.", "issn": "1089-8638", "volume": "426", "issue": "11", "pages": "2246-2254", "issn-l": "0022-2836"}, "abstract": "The increasing number of solved membrane protein structures has led to the recognition of a common feature in a large fraction of the small-molecule transporters: inverted repeat structures, formed by two fused homologous membrane domains with opposite orientation in the membrane. An evolutionary pathway in which the ancestral state is a single gene encoding a dual-topology membrane protein capable of forming antiparallel homodimers has been posited. A gene duplication event enables the evolution of two oppositely orientated proteins that form antiparallel heterodimers. Finally, fusion of the two genes generates an internally duplicated transporter with two oppositely orientated membrane domains. Strikingly, however, in the small multidrug resistance (SMR) family of transporters, no fused, internally duplicated proteins have been found to date. Here, we have analyzed fused versions of the dual-topology transporter EmrE, a member of the SMR family, by blue-native PAGE and in vivo activity measurements. We find that fused constructs give rise to both intramolecular inverted repeat structures and competing intermolecular dimers of varying activity. The formation of several intramolecularly and intermolecularly paired species indicates that a gene fusion event may lower the overall amount of active protein, possibly explaining the apparent absence of fused SMR proteins in nature. ", "doi": "10.1016/j.jmb.2014.03.012", "pmid": "24690367", "labels": {"Affiliated researcher": null}, "xrefs": [{"db": "pii", "key": "S0022-2836(14)00157-0"}], "notes": [], "created": "2018-12-05T11:53:42.114Z", "modified": "2018-12-05T11:53:42.135Z"}, {"entity": "publication", "iuid": "0bc6178b00974d25811aa20be105f42f", "links": {"self": {"href": "https://publications-affiliated.scilifelab.se/publication/0bc6178b00974d25811aa20be105f42f.json"}, "display": {"href": "https://publications-affiliated.scilifelab.se/publication/0bc6178b00974d25811aa20be105f42f"}}, "title": "In vivo trp scanning of the small multidrug resistance protein EmrE confirms 3D structure models'.", "authors": [{"family": "Lloris-Garcer\u00e1", "given": "Pilar", "initials": "P"}, {"family": "Slusky", "given": "Joanna S G", "initials": "JS"}, {"family": "Sepp\u00e4l\u00e4", "given": "Susanna", "initials": "S"}, {"family": "Prie\u00df", "given": "Marten", "initials": "M"}, {"family": "Sch\u00e4fer", "given": "Lars V", "initials": "LV"}, {"family": "von Heijne", "given": "Gunnar", "initials": "G"}], "type": "journal article", "published": "2013-11-15", "journal": {"title": "J. Mol. Biol.", "issn": "1089-8638", "volume": "425", "issue": "22", "pages": "4642-4651", "issn-l": "0022-2836"}, "abstract": "The quaternary structure of the homodimeric small multidrug resistance protein EmrE has been studied intensely over the past decade. Structural models derived from both two- and three-dimensional crystals show EmrE as an anti-parallel homodimer. However, the resolution of the structures is rather low and their relevance for the in vivo situation has been questioned. Here, we have challenged the available structural models by a comprehensive in vivo Trp scanning of all four transmembrane helices in EmrE. The results are in close agreement with the degree of lipid exposure of individual residues predicted from coarse-grained molecular dynamics simulations of the anti-parallel dimeric structure obtained by X-ray crystallography, strongly suggesting that the X-ray structure provides a good representation of the active in vivo form of EmrE. ", "doi": "10.1016/j.jmb.2013.07.039", "pmid": "23920359", "labels": {"Affiliated researcher": null}, "xrefs": [{"db": "pii", "key": "S0022-2836(13)00500-7"}], "notes": [], "created": "2018-12-05T11:23:15.170Z", "modified": "2018-12-05T11:23:15.188Z"}, {"entity": "publication", "iuid": "718ab2e5702745328237bcd4fe43cb15", "links": {"self": {"href": "https://publications-affiliated.scilifelab.se/publication/718ab2e5702745328237bcd4fe43cb15.json"}, "display": {"href": "https://publications-affiliated.scilifelab.se/publication/718ab2e5702745328237bcd4fe43cb15"}}, "title": "Quantitative analysis of SecYEG-mediated insertion of transmembrane \u03b1-helices into the bacterial inner membrane.", "authors": [{"family": "Ojemalm", "given": "Karin", "initials": "K"}, {"family": "Botelho", "given": "Salom\u00e9 Calado", "initials": "SC"}, {"family": "St\u00fcdle", "given": "Chiara", "initials": "C"}, {"family": "von Heijne", "given": "Gunnar", "initials": "G"}], "type": "journal article", "published": "2013-08-09", "journal": {"title": "J. Mol. Biol.", "issn": "1089-8638", "volume": "425", "issue": "15", "pages": "2813-2822", "issn-l": "0022-2836"}, "abstract": "Most integral membrane proteins, both in prokaryotic and eukaryotic cells, are co-translationally inserted into the membrane via Sec-type translocons: the SecYEG complex in prokaryotes and the Sec61 complex in eukaryotes. The contributions of individual amino acids to the overall free energy of membrane insertion of single transmembrane \u03b1-helices have been measured for Sec61-mediated insertion into the endoplasmic reticulum (ER) membrane (Nature 450:1026-1030) but have not been systematically determined for SecYEG-mediated insertion into the bacterial inner membrane. We now report such measurements, carried out in Escherichia coli. Overall, there is a good correlation between the results found for the mammalian ER and the E. coli inner membrane, but the hydrophobicity threshold for SecYEG-mediated insertion is distinctly lower than that for Sec61-mediated insertion.", "doi": "10.1016/j.jmb.2013.04.025", "pmid": "23659793", "labels": {"Affiliated researcher": null}, "xrefs": [{"db": "pii", "key": "S0022-2836(13)00273-8"}], "notes": [], "created": "2018-12-05T09:42:33.342Z", "modified": "2018-12-05T09:42:33.361Z"}, {"entity": "publication", "iuid": "432973158ff5433f8a2c35f612186a16", "links": {"self": {"href": "https://publications-affiliated.scilifelab.se/publication/432973158ff5433f8a2c35f612186a16.json"}, "display": {"href": "https://publications-affiliated.scilifelab.se/publication/432973158ff5433f8a2c35f612186a16"}}, "title": "Hieranoid: hierarchical orthology inference.", "authors": [{"family": "Schreiber", "given": "Fabian", "initials": "F"}, {"family": "Sonnhammer", "given": "Erik L L", "initials": "ELL"}], "type": "journal article", "published": "2013-06-12", "journal": {"title": "J. Mol. Biol.", "issn": "1089-8638", "volume": "425", "issue": "11", "pages": "2072-2081", "issn-l": "0022-2836"}, "abstract": "An accurate inference of orthologs is essential in many research fields such as comparative genomics, molecular evolution, and genome annotation. Existing methods for genome-scale orthology inference are mostly based on all-versus-all similarity searches that scale quadratically with the number of species. This limits their application to the increasing number of available large-scale datasets. Here, we present Hieranoid, a new orthology inference method using a hierarchical approach. Hieranoid performs pairwise orthology analysis using InParanoid at each node in a guide tree as it progresses from its leaves to the root. This concept reduces the total runtime complexity from a quadratic to a linear function of the number of species. The tree hierarchy provides a natural structure in multi-species ortholog groups, and the aggregation of multiple sequences allows for multiple alignment similarity searching techniques, which can yield more accurate ortholog groups. Using the recently published orthobench benchmark, Hieranoid showed the overall best performance. Our progressive approach presents a new way to infer orthologs that combines efficient graph-based methodology with aspects of compute-intensive tree-based methods. The linear scaling with the number of species is a major advantage for large-scale applications and makes Hieranoid well suited to cope with vast amounts of sequenced genomes in the future. Hieranoid is an open source and can be downloaded at Hieranoid.sbc.su.se.", "doi": "10.1016/j.jmb.2013.02.018", "pmid": "23485417", "labels": {"Affiliated researcher": null}, "xrefs": [{"db": "pii", "key": "S0022-2836(13)00120-4"}], "notes": [], "created": "2018-12-05T09:39:06.493Z", "modified": "2018-12-05T09:39:06.511Z"}, {"entity": "publication", "iuid": "e50a44a102e54b5b86c65bd8f754711c", "links": {"self": {"href": "https://publications-affiliated.scilifelab.se/publication/e50a44a102e54b5b86c65bd8f754711c.json"}, "display": {"href": "https://publications-affiliated.scilifelab.se/publication/e50a44a102e54b5b86c65bd8f754711c"}}, "title": "Charge pair interactions in transmembrane helices and turn propensity of the connecting sequence promote helical hairpin insertion.", "authors": [{"family": "Ba\u00f1\u00f3-Polo", "given": "Manuel", "initials": "M"}, {"family": "Mart\u00ednez-Gil", "given": "Luis", "initials": "L"}, {"family": "Wallner", "given": "Bj\u00f6rn", "initials": "B"}, {"family": "Nieva", "given": "Jos\u00e9 L", "initials": "JL"}, {"family": "Elofsson", "given": "Arne", "initials": "A"}, {"family": "Mingarro", "given": "Ismael", "initials": "I"}], "type": "journal article", "published": "2013-02-22", "journal": {"title": "J. Mol. Biol.", "issn": "1089-8638", "volume": "425", "issue": "4", "pages": "830-840", "issn-l": "0022-2836"}, "abstract": "\u03b1-Helical hairpins, consisting of a pair of closely spaced transmembrane (TM) helices that are connected by a short interfacial turn, are the simplest structural motifs found in multi-spanning membrane proteins. In naturally occurring hairpins, the presence of polar residues is common and predicted to complicate membrane insertion. We postulate that the pre-packing process offsets any energetic cost of allocating polar and charged residues within the hydrophobic environment of biological membranes. Consistent with this idea, we provide here experimental evidence demonstrating that helical hairpin insertion into biological membranes can be driven by electrostatic interactions between closely separated, poorly hydrophobic sequences. Additionally, we observe that the integral hairpin can be stabilized by a short loop heavily populated by turn-promoting residues. We conclude that the combined effect of TM-TM electrostatic interactions and tight turns plays an important role in generating the functional architecture of membrane proteins and propose that helical hairpin motifs can be acquired within the context of the Sec61 translocon at the early stages of membrane protein biosynthesis. Taken together, these data further underline the potential complexities involved in accurately predicting TM domains from primary structures.", "doi": "10.1016/j.jmb.2012.12.001", "pmid": "23228331", "labels": {"Affiliated researcher": null}, "xrefs": [{"db": "pii", "key": "S0022-2836(12)00915-1"}], "notes": [], "created": "2018-12-05T09:39:21.711Z", "modified": "2018-12-05T09:39:21.732Z"}], "created": "2018-12-05T08:37:01.369Z", "modified": "2020-11-27T13:12:52.301Z"}