An Acrobatic Substrate Metamorphosis Reveals a Requirement for Substrate Conformational Dynamics in Trypsin Proteolysis

Kayode, Olumide; Wang, Ruiying; Pendlebury, Devon F.; Cohen, Itay; Henin, Rachel D.; Hockla, Alexandra; Soares, Alexei S.; Papo, Niv; Caulfield, Thomas R.; Radisky, Evette S.

doi:10.1074/jbc.M116.758417

Title: An Acrobatic Substrate Metamorphosis Reveals a Requirement for Substrate Conformational Dynamics in Trypsin Proteolysis

Journal Article · Thu Nov 03 00:00:00 EDT 2016 · Journal of Biological Chemistry

DOI:https://doi.org/10.1074/jbc.M116.758417· OSTI ID:1351724

Kayode, Olumide ^[1]; Wang, Ruiying ^[1]; Pendlebury, Devon F. ^[1]; Cohen, Itay ^[2]; Henin, Rachel D. ^[1]; Hockla, Alexandra ^[1]; Soares, Alexei S. ^[3]; Papo, Niv ^[2]; Caulfield, Thomas R. ^[4]; Radisky, Evette S. ^[1]

Mayo Clinic, Jacksonville, Florida (United States). College of Medicine, Dept. of Cancer Biology
Ben-Gurion Univ. of the Negev, Beer-Sheva (Israel). Dept. of Biotechnology Engineering and the National Inst. of Biotechnology
Brookhaven National Lab. (BNL), Upton, NY (United States). Photon Sciences Directorate
Mayo Clinic, Jacksonville, Florida (United States). College of Medicine, Dept. of Neuroscience

The molecular basis of enzyme catalytic power and specificity derives from dynamic interactions between enzyme and substrate during catalysis. While considerable effort has been devoted to understanding how conformational dynamics within enzymes affect catalysis, the role of conformational dynamics within protein substrates has not been addressed. Here in this paper, we examine the importance of substrate dynamics in the cleavage of Kunitz-BPTI protease inhibitors by mesotrypsin, finding that the varied conformational dynamics of structurally similar substrates can profoundly impact the rate of catalysis. A 1.4 Å crystal structure of a mesotrypsin-product complex formed with a rapidly cleaved substrate reveals a dramatic conformational change in the substrate upon proteolysis. Using long all-atom molecular dynamics simulations of acyl-enzyme intermediates with proteolysis rates spanning three orders of magnitude, we identify global and local dynamic features of substrates on the ns-μs timescale that correlate with enzymatic rates and explain differential susceptibility to proteolysis. By integrating multiple enhanced sampling methods for molecular dynamics, we model a viable conformational pathway between substratelike and product-like states, linking substrate dynamics on the ns-μs timescale with large collective substrate motions on the much slower timescale of catalysis. Our findings implicate substrate flexibility as a critical determinant of catalysis.

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Research Organization:: Brookhaven National Laboratory (BNL), Upton, NY (United States)

Sponsoring Organization:: USDOE Office of Science (SC), Basic Energy Sciences (BES)

Grant/Contract Number:: SC0012704

OSTI ID:: 1351724

Report Number(s):: BNL-113701-2017-JA

Journal Information:: Journal of Biological Chemistry, Vol. 291, Issue 51; ISSN 0021-9258

Publisher:: American Society for Biochemistry and Molecular BiologyCopyright Statement

Country of Publication:: United States

Language:: English

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Cited by: 17 works

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59 BASIC BIOLOGICAL SCIENCES
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protein conformation
serine protease
protease inhibitor
proteolysis
enzyme catalysis
protein structure
crystal structure
molecular dynamics
molecular modeling

Title: An Acrobatic Substrate Metamorphosis Reveals a Requirement for Substrate Conformational Dynamics in Trypsin Proteolysis

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