TY - JOUR
T1 - The effect of dimerization and ligand binding on the dynamics of Kaposi's sarcoma-associated herpesvirus protease
AU - Bern, David
AU - Tobi, Dror
N1 - Publisher Copyright:
© 2022 The Authors. Proteins: Structure, Function, and Bioinformatics published by Wiley Periodicals LLC.
PY - 2022/6
Y1 - 2022/6
N2 - The Kaposi's sarcoma-associated herpesvirus protease is essential for virus maturation. This protease functions under allosteric regulation that establishes its enzymatic activity upon dimerization. It exists in equilibrium between an inactive monomeric state and an active, weakly associating, dimeric state that is stabilized upon ligand binding. The dynamics of the protease dimer and its monomer were studied using the Gaussian network model and the anisotropic network model, and its role in mediating the allosteric regulation is demonstrated. We show that the dimer is composed of five dynamical domains. The central domain is formed upon dimerization and composed of helix five of each monomer, in addition to proximal and distal domains of each monomer. Dimerization reduces the mobility of the central domains and increases the mobility of the distal domains, in particular the binding site within them. The three slowest ANM modes of the dimer assist the protease in ligand binding, motion of the conserved Arg142 and Arg143 toward the oxyanion, and reducing the activation barrier for the tetrahedral transition state by stretching the bond that is cleaved by the protease. In addition, we show that ligand binding reduces the motion of helices α1 and α5 at the interface and explain how ligand binding can stabilize the dimer.
AB - The Kaposi's sarcoma-associated herpesvirus protease is essential for virus maturation. This protease functions under allosteric regulation that establishes its enzymatic activity upon dimerization. It exists in equilibrium between an inactive monomeric state and an active, weakly associating, dimeric state that is stabilized upon ligand binding. The dynamics of the protease dimer and its monomer were studied using the Gaussian network model and the anisotropic network model, and its role in mediating the allosteric regulation is demonstrated. We show that the dimer is composed of five dynamical domains. The central domain is formed upon dimerization and composed of helix five of each monomer, in addition to proximal and distal domains of each monomer. Dimerization reduces the mobility of the central domains and increases the mobility of the distal domains, in particular the binding site within them. The three slowest ANM modes of the dimer assist the protease in ligand binding, motion of the conserved Arg142 and Arg143 toward the oxyanion, and reducing the activation barrier for the tetrahedral transition state by stretching the bond that is cleaved by the protease. In addition, we show that ligand binding reduces the motion of helices α1 and α5 at the interface and explain how ligand binding can stabilize the dimer.
KW - Gaussian network model
KW - Kaposi sarcoma
KW - allostery
KW - anisotropic network model
KW - comparative dynamics
KW - herpesvirus protease
KW - normal mode analysis
KW - normal modes alignment
KW - protein dynamics
KW - varicella-zoster virus
UR - http://www.scopus.com/inward/record.url?scp=85124462583&partnerID=8YFLogxK
U2 - 10.1002/prot.26307
DO - 10.1002/prot.26307
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C2 - 35084062
AN - SCOPUS:85124462583
SN - 0887-3585
VL - 90
SP - 1267
EP - 1277
JO - Proteins: Structure, Function and Bioinformatics
JF - Proteins: Structure, Function and Bioinformatics
IS - 6
ER -