{"entity": "publication", "iuid": "e2601241d2fd46c4b456af43fedf0f3c", "timestamp": "2026-09-24T14:44:49.223Z", "links": {"self": {"href": "https://publications-affiliated.scilifelab.se/publication/e2601241d2fd46c4b456af43fedf0f3c.json"}, "display": {"href": "https://publications-affiliated.scilifelab.se/publication/e2601241d2fd46c4b456af43fedf0f3c"}}, "title": "Single Residue on the WPD-Loop Affects the pH Dependency of Catalysis in Protein Tyrosine Phosphatases.", "authors": [{"family": "Shen", "given": "Ruidan", "initials": "R"}, {"family": "Crean", "given": "Rory M", "initials": "RM"}, {"family": "Johnson", "given": "Sean J", "initials": "SJ", "orcid": "0000-0001-7992-2494", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/4229ef82708c44c5bb6a3fabf913c44b.json"}}, {"family": "Kamerlin", "given": "Shina C L", "initials": "SCL", "orcid": "0000-0002-3190-1173", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/c4540c85432f4cdf952b0ef7cfe1d875.json"}}, {"family": "Hengge", "given": "Alvan C", "initials": "AC", "orcid": "0000-0002-5696-2087", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/43fb9bec035e46c4a63263aded78a78b.json"}}], "type": "journal article", "published": "2021-05-24", "journal": {"title": "JACS Au", "issn": "2691-3704", "volume": "1", "issue": "5", "pages": "646-659", "issn-l": null}, "abstract": "Catalysis by protein tyrosine phosphatases (PTPs) relies on the motion of a flexible protein loop (the WPD-loop) that carries a residue acting as a general acid/base catalyst during the PTP-catalyzed reaction. The orthogonal substitutions of a noncatalytic residue in the WPD-loops of YopH and PTP1B result in shifted pH-rate profiles from an altered kinetic pK a of the nucleophilic cysteine. Compared to wild type, the G352T YopH variant has a broadened pH-rate profile, similar activity at optimal pH, but significantly higher activity at low pH. Changes in the corresponding PTP1B T177G variant are more modest and in the opposite direction, with a narrowed pH profile and less activity in the most acidic range. Crystal structures of the variants show no structural perturbations but suggest an increased preference for the WPD-loop-closed conformation. Computational analysis confirms a shift in loop conformational equilibrium in favor of the closed conformation, arising from a combination of increased stability of the closed state and destabilization of the loop-open state. Simulations identify the origins of this population shift, revealing differences in the flexibility of the WPD-loop and neighboring regions. Our results demonstrate that changes to the pH dependency of catalysis by PTPs can result from small changes in amino acid composition in their WPD-loops affecting only loop dynamics and conformational equilibrium. The perturbation of kinetic pK a values of catalytic residues by nonchemical processes affords a means for nature to alter an enzyme's pH dependency by a less disruptive path than altering electrostatic networks around catalytic residues themselves.", "doi": "10.1021/jacsau.1c00054", "pmid": "34308419", "labels": [], "xrefs": [{"db": "pmc", "key": "PMC8297725"}], "notes": [], "created": "2026-09-23T10:03:46.425Z", "modified": "2026-09-23T10:42:19.860Z"}