Loop Dynamics and Enzyme Catalysis in Protein Tyrosine Phosphatases
Crean, Rory M. ; Biler, Michal ; Van Der Kamp, Marc W. ; Hengge, Alvan C. and Kamerlin, Shina C.L. LU
(2021)
In Journal of the American Chemical Society
143(10).
p.3830-3845
- Abstract
Protein tyrosine phosphatases (PTPs) play an important role in cellular signaling and have been implicated in human cancers, diabetes, and obesity. Despite shared catalytic mechanisms and transition states for the chemical steps of catalysis, catalytic rates within the PTP family vary over several orders of magnitude. These rate differences have been implied to arise from differing conformational dynamics of the closure of a protein loop, the WPD-loop, which carries a catalytically critical residue. The present work reports computational studies of the human protein tyrosine phosphatase 1B (PTP1B) and YopH from Yersinia pestis, for which NMR has demonstrated a link between their respective rates of WPD-loop motion and catalysis rates,... (More)
Protein tyrosine phosphatases (PTPs) play an important role in cellular signaling and have been implicated in human cancers, diabetes, and obesity. Despite shared catalytic mechanisms and transition states for the chemical steps of catalysis, catalytic rates within the PTP family vary over several orders of magnitude. These rate differences have been implied to arise from differing conformational dynamics of the closure of a protein loop, the WPD-loop, which carries a catalytically critical residue. The present work reports computational studies of the human protein tyrosine phosphatase 1B (PTP1B) and YopH from Yersinia pestis, for which NMR has demonstrated a link between their respective rates of WPD-loop motion and catalysis rates, which differ by an order of magnitude. We have performed detailed structural analysis, both conventional and enhanced sampling simulations of their loop dynamics, as well as empirical valence bond simulations of the chemical step of catalysis. These analyses revealed the key residues and structural features responsible for these differences, as well as the residues and pathways that facilitate allosteric communication in these enzymes. Curiously, our wild-type YopH simulations also identify a catalytically incompetent hyper-open conformation of its WPD-loop, sampled as a rare event, previously only experimentally observed in YopH-based chimeras. The effect of differences within the WPD-loop and its neighboring loops on the modulation of loop dynamics, as revealed in this work, may provide a facile means for the family of PTP enzymes to respond to environmental changes and regulate their catalytic activities.
(Less)
- author
- Crean, Rory M.
; Biler, Michal
; Van Der Kamp, Marc W.
; Hengge, Alvan C.
and Kamerlin, Shina C.L.
LU
- publishing date
- 2021
- type
- Contribution to journal
- publication status
- published
- in
- Journal of the American Chemical Society
- volume
- 143
- issue
- 10
- pages
- 16 pages
- publisher
- The American Chemical Society (ACS)
- external identifiers
-
- pmid:33661624
- scopus:85103226460
- ISSN
- 0002-7863
- DOI
- 10.1021/jacs.0c11806
- language
- English
- LU publication?
- no
- additional info
- Publisher Copyright: © 2021 The Authors. Published by American Chemical Society.
- id
- 3a34172f-a20c-4253-b216-d184830f9bd4
- date added to LUP
- 2025-01-16 14:08:04
- date last changed
- 2025-08-01 06:57:52
@article{3a34172f-a20c-4253-b216-d184830f9bd4,
abstract = {{<p>Protein tyrosine phosphatases (PTPs) play an important role in cellular signaling and have been implicated in human cancers, diabetes, and obesity. Despite shared catalytic mechanisms and transition states for the chemical steps of catalysis, catalytic rates within the PTP family vary over several orders of magnitude. These rate differences have been implied to arise from differing conformational dynamics of the closure of a protein loop, the WPD-loop, which carries a catalytically critical residue. The present work reports computational studies of the human protein tyrosine phosphatase 1B (PTP1B) and YopH from Yersinia pestis, for which NMR has demonstrated a link between their respective rates of WPD-loop motion and catalysis rates, which differ by an order of magnitude. We have performed detailed structural analysis, both conventional and enhanced sampling simulations of their loop dynamics, as well as empirical valence bond simulations of the chemical step of catalysis. These analyses revealed the key residues and structural features responsible for these differences, as well as the residues and pathways that facilitate allosteric communication in these enzymes. Curiously, our wild-type YopH simulations also identify a catalytically incompetent hyper-open conformation of its WPD-loop, sampled as a rare event, previously only experimentally observed in YopH-based chimeras. The effect of differences within the WPD-loop and its neighboring loops on the modulation of loop dynamics, as revealed in this work, may provide a facile means for the family of PTP enzymes to respond to environmental changes and regulate their catalytic activities.</p>}},
author = {{Crean, Rory M. and Biler, Michal and Van Der Kamp, Marc W. and Hengge, Alvan C. and Kamerlin, Shina C.L.}},
issn = {{0002-7863}},
language = {{eng}},
number = {{10}},
pages = {{3830--3845}},
publisher = {{The American Chemical Society (ACS)}},
series = {{Journal of the American Chemical Society}},
title = {{Loop Dynamics and Enzyme Catalysis in Protein Tyrosine Phosphatases}},
url = {{http://dx.doi.org/10.1021/jacs.0c11806}},
doi = {{10.1021/jacs.0c11806}},
volume = {{143}},
year = {{2021}},
}