title: Mechanisms for allosteric activation of protease DegS by ligand binding and oligomerization as revealed from molecular dynamics simulations.
abstract: A local perturbation of a protein may lead to functional changes at some distal site, a phenomenon denoted as allostery. Here, we study the allosteric control of a protease using molecular dynamics simulations. The system considered is the bacterial protein DegS which includes a protease domain activated on ligand binding to an adjacent PDZ domain. Starting from crystallographic structures of DegS homo-trimers, we perform simulations of the ligand-free and -bound state of DegS at equilibrium. Considering a single protomer only, the trimeric state was mimicked by applying restraints on the residues in contact with other protomers in the DegS trimer. In addition, the bound state was also simulated without any restraints to mimic the monomer. Our results suggest that not only ligand release but also disassembly of a DegS trimer inhibits proteolytic activity. Considering various observables for structural changes, we infer allosteric pathways from the interface with other protomers to the active site. Moreover, we study how ligand release leads to (i) catalytically relevant changes involving residues 199-201 and (ii) a transition from a stretched to a bent conformation for residues 217-219 (which prohibits proper substrate binding). Finally, based on ligand-induced Cαshifts we identify residues in contact with other protomers in the DegS trimer that likely transduce the perturbation from ligand release from a given protomer to adjacent protomers. These residues likely play a key role in the experimentally known effect of ligand release from a protomer on the proteolytic activity of the other protomers. Proteins 2016; 84:1690-1705. © 2016 Wiley Periodicals, Inc.
authors.affiliation: Biomolecular Dynamics Group, Institute of Physics, Albert Ludwigs University, Hermann-Herder-Str. 3, Freiburg, 79104, Germany.
authors.forename: Cheng
authors.initials: C
authors.lastname: Lu
authors.affiliation: Biomolecular Dynamics Group, Institute of Physics, Albert Ludwigs University, Hermann-Herder-Str. 3, Freiburg, 79104, Germany.
authors.forename: Gerhard
authors.initials: G
authors.lastname: Stock
authors.affiliation: Biomolecular Dynamics Group, Institute of Physics, Albert Ludwigs University, Hermann-Herder-Str. 3, Freiburg, 79104, Germany. volker.knecht@physik.uni-freiburg.de.
authors.forename: Volker
authors.initials: V
authors.lastname: Knecht
mesh_terms: D000494:Allosteric Regulation; D000495:Allosteric Site; D020816:Amino Acid Motifs; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D004926:Escherichia coli / Q000737:chemistry* / Q000378:metabolism; D029968:Escherichia coli Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D007700:Kinetics; D008024:Ligands; D056004:Molecular Dynamics Simulation; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D055503:Protein Multimerization; D017433:Protein Structure, Secondary; D013329:Structure-Activity Relationship; D013816:Thermodynamics
chemical_list: D029968:Escherichia coli Proteins; D008024:Ligands; C489349:degS protein, Escherichia coli
keywords: Cα shifts; PDZ domain; allosteric communication; backbone dihedral angles; interresidue contacts; intramolecular signaling; nonequilibrium MD simulations