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Insights into the importance of WPD-loop sequence for activity and structure in protein tyrosine phosphatases
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- Shen, Ruidan (author)
- Utah State Univ, Dept Chem & Biochem, Logan, UT 84322 USA.
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- Crean, Rory M. (author)
- Uppsala universitet,Biokemi,Science for Life Laboratory, SciLifeLab
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- Olsen, Keith J. (author)
- Utah State Univ, Dept Chem & Biochem, Logan, UT 84322 USA.
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- Corbella Morató, Marina (author)
- Uppsala universitet,Biokemi,Science for Life Laboratory, SciLifeLab
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- Calixto, Ana R. (author)
- Uppsala universitet,Biokemi,Science for Life Laboratory, SciLifeLab
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- Richan, Teisha (author)
- Utah State Univ, Dept Chem & Biochem, Logan, UT 84322 USA.
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- Brandao, Tiago A. S. (author)
- Univ Fed Minas Gerais, Dept Quim, ICEX, BR-31270901 Belo Horizonte, MG, Brazil.
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- Berry, Ryan D. (author)
- Utah State Univ, Dept Chem & Biochem, Logan, UT 84322 USA.
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- Tolman, Alex (author)
- Utah State Univ, Dept Chem & Biochem, Logan, UT 84322 USA.
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- Loria, J. Patrick (author)
- Yale Univ, Dept Chem, 225 Prospect St, New Haven, CT 06520 USA.;Yale Univ, Dept Mol Biophys & Biochem, 266 Whitney Ave, New Haven, CT 06520 USA.
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- Johnson, Sean J. (author)
- Utah State Univ, Dept Chem & Biochem, Logan, UT 84322 USA.
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- Kamerlin, Shina C. L., 1981- (author)
- Uppsala universitet,Science for Life Laboratory, SciLifeLab,Biokemi,Georgia Inst Technol, Sch Chem & Biochem, 901 Atlantic Dr NW, Atlanta, GA 30332 USA.
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- Hengge, Alvan C. (author)
- Utah State Univ, Dept Chem & Biochem, Logan, UT 84322 USA.
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Utah State Univ, Dept Chem & Biochem, Logan, UT 84322 USA Biokemi (creator_code:org_t)
- 2022
- 2022
- English.
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In: Chemical Science. - : Royal Society of Chemistry. - 2041-6520 .- 2041-6539. ; 13:45, s. 13524-13540
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https://doi.org/10.1...
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Abstract
Subject headings
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- Protein tyrosine phosphatases (PTPs) possess a conserved mobile catalytic loop, the WPD-loop, which brings an aspartic acid into the active site where it acts as an acid/base catalyst. Prior experimental and computational studies, focused on the human enzyme PTP1B and the PTP from Yersinia pestis, YopH, suggested that loop conformational dynamics are important in regulating both catalysis and evolvability. We have generated a chimeric protein in which the WPD-loop of YopH is transposed into PTP1B, and eight chimeras that systematically restored the loop sequence back to native PTP1B. Of these, four chimeras were soluble and were subjected to detailed biochemical and structural characterization, and a computational analysis of their WPD-loop dynamics. The chimeras maintain backbone structural integrity, with somewhat slower rates than either wild-type parent, and show differences in the pH dependency of catalysis, and changes in the effect of Mg2+. The chimeric proteins' WPD-loops differ significantly in their relative stability and rigidity. The time required for interconversion, coupled with electrostatic effects revealed by simulations, likely accounts for the activity differences between chimeras, and relative to the native enzymes. Our results further the understanding of connections between enzyme activity and the dynamics of catalytically important groups, particularly the effects of non-catalytic residues on key conformational equilibria.
Subject headings
- NATURVETENSKAP -- Biologi -- Biokemi och molekylärbiologi (hsv//swe)
- NATURAL SCIENCES -- Biological Sciences -- Biochemistry and Molecular Biology (hsv//eng)
Publication and Content Type
- ref (subject category)
- art (subject category)
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- By the author/editor
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Shen, Ruidan
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Crean, Rory M.
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Olsen, Keith J.
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Corbella Morató, ...
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Calixto, Ana R.
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Richan, Teisha
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show more...
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Brandao, Tiago A ...
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Berry, Ryan D.
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Tolman, Alex
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Loria, J. Patric ...
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Johnson, Sean J.
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Kamerlin, Shina ...
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Hengge, Alvan C.
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- About the subject
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- NATURAL SCIENCES
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NATURAL SCIENCES
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and Biological Scien ...
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and Biochemistry and ...
- Articles in the publication
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Chemical Science
- By the university
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Uppsala University