ChemRxiv
These are preliminary reports that have not been peer-reviewed. They should not be regarded as conclusive, guide clinical practice/health-related behavior, or be reported in news media as established information. For more information, please see our FAQs.
1/1
2 files

Loop Dynamics and Enzyme Catalysis in Protein Tyrosine Phosphatases

preprint
submitted on 10.11.2020, 18:58 and posted on 12.11.2020, 12:46 by Rory Crean, Michal Biler, Marc van der Kamp, Alvan C. Hengge, Shina Caroline Lynn Kamerlin

Protein tyrosine phosphatases (PTPs) play an important role in cellular signalling 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 both 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 neighbouring 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.

Funding

Carl Tryggers Foundation for Scientific Research CTS 19:172

Knut and Alice Wallenberg Foundation 2018.0140

Human Frontier Science Program RGP0041/2017

Swedish Research Council 2019-03499

BBSRC David Phillips Fellowship BB/M026280/1

Swedish National Infrastructure for Computing 018/2-3, 2019/2-1, 2019/3-258 and 2020/5-250

History

Email Address of Submitting Author

lynn.kamerlin@kemi.uu.se

Institution

Uppsala University

Country

Sweden

ORCID For Submitting Author

orcid.org/0000-0002-3190-1173

Declaration of Conflict of Interest

No conflict of interest.

Version Notes

Version 1.0

Exports