The Q41R mutation in the HCV-protease enhances the reactivity towards MAVS by suppressing non-reactive pathways

Date

2022-01-01

Author

Zheng, Chen
Schneider, Markus
Marıon, Antoıne
Antes, Iris

Metadata

Show full item record

This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.

Item Usage Stats

218
views

0
downloads

Recent experimental findings pointed out a new mutation in the HCV protease, Q41R, responsible for a significant enhancement of the enzyme's reactivity towards the mitochondrial antiviral-signaling protein (MAVS). The Q41R mutation is located rather far from the active site, and its involvement in the overall reaction mechanism is thus unclear. We used classical molecular dynamics and QM/MM to study the acylation reaction of HCV NS3/4A protease variants bound to MAVS and the NS4A/4B substrate and uncovered the indirect mechanism by which the Q41R mutation plays a critical role in the efficient cleavage of the substrate. Our simulations reveal that there are two major conformations of the MAVS H1 '(p) residue for the wild type protease and only one conformation for the Q41R mutant. The conformational space of H1 '(p) is restricted by the Q41R mutation due to a pi-pi stacking between H1 '(p) and R41 as well as a strong hydrogen bond between the backbone of H57 and the side chain of R41. Further QM/MM calculations indicate that the complex with the conformation ruled out by the Q41R substitution is a non-reactive species due to its higher free energy barrier for the acylation reaction. Based on our calculations, we propose a kinetic mechanism that explains experimental data showing an increase of apparent rate constants for MAVS cleavage in Q41R mutants. Our model predicts that the non-reactive conformation of the enzyme-substrate complex modulates reaction kinetics like an uncompetitive inhibitor.

URI

https://hdl.handle.net/11511/96018

Journal

PHYSICAL CHEMISTRY CHEMICAL PHYSICS

DOI

https://doi.org/10.1039/d1cp05002h

Collections

Department of Chemistry, Article

Suggestions

OpenMETU
Core

AN ONCOGENIC ISOFORM SWITCH LEADS TO HNRNPA1 OVEREXPRESSION IN TRIPLE NEGATIVE BREAST CANCER Erdem, Murat; Erson Bensan, Ayşe Elif; Department of Biology (2022-8-05) HNRNPA1 is one of the most abundant and ubiquitously expressed nuclear proteins and plays a significant role in RNA biology. It has many diverse functions in cellular nucleic acid metabolisms, including mRNA transport, miRNA maturation, and telomere maintenance. Emerging evidence suggest HNRNPA1 to be an important RNA binding protein (RBP) to regulate various RNA related processes in cancer cells. However, deregulation of HNRNPA1 expression and its action mechanisms are unclear in breast cancers. The study...
Overexpression of a serine alkaline protease gene in Bacillus licheniformis and its impact on the metabolic reaction network Çalık, Pınar; Oliver, SG; Ozdamar, TH (Elsevier BV, 2003-05-20) This work reports on cloning of serine alkaline protease (SAP) encoding gene subC to a multi-copy plasmid and its expression in Bacillus licheniformis with the quantitative impact of overexpression of the subC gene on metabolic flux distributions. Bioprocess characteristics of the wild-type and the recombinant B. licheniformis were investigated in a defined simple synthetic medium with glucose as the sole carbon source under well-defined bioreactor-operation conditions. Significant physiological changes wer...
A new ZTL-type F-box functions as a positive regulator in disease resistance: VIGS analysis in barley against powdery mildew Dagdas, Yasin Fatih; Dagdas, Gulay; Unver, Turgay; Akkaya, Mahinur (2009-01-01) In our previous studies, we found a new Zeitlupe (ZTL) type F-box protein which is expressed at a higher level upon avirulent pathogen infection (Bozkurt et al., 2007). F-box proteins mark the proteins to be degraded through 26S proteasome system by ubiquitination. Since the information on the role of ubiquitin mediated proteolysis in disease responses is advancing rapidly, we sought to understand the way which F-box functions in resistance response as part of ubiquitin-proteasome pathway. Interestingly, in...
The effect of cysteine-43 mutation on thermostability and kinetic properties of citrate synthase from Thermoplasma acidophilum Kocabıyık, Semra; Russel, RJM; Danson, MJ; Hough, DW (Elsevier BV, 1996-07-05) In this study, we have substituted serine-43 by cysteine in the recombinant citrate synthase from a moderately thermophilic Archaeon Thermoplasma acidophilum, for site-specific attachment of labels and have investigated the effects of this mutation on the biochemical properties and thermal stability of the enzyme. Both wild-type and the mutant enzymes were purified to homogenity using affinity chromatography on Matrex Gel Red A. The mutant Thermoplasma citrate synthase is very similar to wild-type citrate s...
The role of bcsE gene in the pathogenicity of Salmonella Ozdemir, Caner; AKÇELİK, NEFİSE; Özdemir, Fatma Neslihan; Evcili, Irem; Kahraman, Tamer; GÜRSEL, İHSAN; AKÇELİK, MUSTAFA (2021-08-01) The effects of the bcsE gene and BcsE protein on bacterial physiology and pathogenicity in SalmonellaTyphimurium and Salmonella Group C1 were investigated. It was observed that biofilm and pellicle formation did not occur in the bcsE gene mutants of wild-type strains. Besides, the 'rdar' (red, dry, rough) biofilm morphotype in wild-type strains changed significantly in the mutants. In terms of the bcsE gene, the swimming and swarming motility in mutant strains showed a dramatic increase compared to the wild...

Citation Formats

C. Zheng, M. Schneider, A. Marıon, and I. Antes, “The Q41R mutation in the HCV-protease enhances the reactivity towards MAVS by suppressing non-reactive pathways,” PHYSICAL CHEMISTRY CHEMICAL PHYSICS, vol. 24, no. 4, pp. 2126–2138, 2022, Accessed: 00, 2022. [Online]. Available: https://hdl.handle.net/11511/96018.