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Single Residue on the WPD-Loop Affects the pH Dependency of Catalysis in Protein Tyrosine Phosphatases
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- Shen, Ruidan (författare)
- Utah State Univ, Dept Chem & Biochem, Logan, UT 84322 USA
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- Crean, Rory M. (författare)
- Uppsala universitet,Biokemi,Science for Life Laboratory, SciLifeLab,Kamerlin
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- Johnson, Sean J. (författare)
- Utah State Univ, Dept Chem & Biochem, Logan, UT 84322 USA
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- Kamerlin, Shina C. L., 1981- (författare)
- Uppsala universitet,Biokemi,Science for Life Laboratory, SciLifeLab,Kamerlin
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- Hengge, Alvan C. (författare)
- Utah State Univ, Dept Chem & Biochem, Logan, UT 84322 USA
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(creator_code:org_t)
- 2021-04-23
- 2021
- Engelska.
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Ingår i: JACS Au. - : American Chemical Society (ACS). - 2691-3704. ; 1:5, s. 646-659
- Relaterad länk:
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https://doi.org/10.1...
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https://uu.diva-port... (primary) (Raw object)
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https://pubs.acs.org...
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https://urn.kb.se/re...
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https://doi.org/10.1...
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Abstract
Ämnesord
Stäng
- 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 pKa 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 pKa 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.
Ämnesord
- NATURVETENSKAP -- Biologi -- Biokemi och molekylärbiologi (hsv//swe)
- NATURAL SCIENCES -- Biological Sciences -- Biochemistry and Molecular Biology (hsv//eng)
Nyckelord
- Protein tyrosine phosphatases
- Enzyme kinetics
- Protein dynamics
- Enzyme catalysis
- Point mutation
- Loop dynamics
- pH dependence
- Molecular dynamics simulations
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- art (ämneskategori)
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