title: Helix unfolding/refolding characterizes the functional dynamics of Staphylococcus aureus Clp protease.
abstract: The ATP-dependent Clp protease (ClpP) plays an essential role not only in the control of protein quality but also in the regulation of bacterial pathogen virulence, making it an attractive target for antibacterial treatment. We have previously determined the crystal structures of Staphylococcus aureus ClpP (SaClpP) in two different states, extended and compressed. To investigate the dynamic switching of ClpP between these states, we performed a series of molecular dynamics simulations. During the structural transition, the long and straight helix E in the extended SaClpP monomer underwent an unfolding/refolding process, resulting in a kinked helix very similar to that in the compressed monomer. As a stable intermediate in the molecular dynamics simulation, the compact state was suggested and subsequently identified in x-ray crystallographic experiment. Our combined studies also determined that Ala(140) acted as a "hinge" during the transition between the extended and compressed states, and Glu(137) was essential for stabilizing the compressed state. Overall, this study provides molecular insights into the dynamics and mechanism of the functional conformation changes of SaClpP. Given the highly conserved sequences of ClpP proteins among different species, these findings potentially reflect a switching mechanism for the dynamic process shared in the whole ClpP family in general and thus aid in better understand the principles of Clp protease assembly and function.
authors.affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Fei
authors.initials: F
authors.lastname: Ye
authors.forename: Jie
authors.initials: J
authors.lastname: Zhang
authors.forename: Hongchuan
authors.initials: H
authors.lastname: Liu
authors.forename: Rolf
authors.initials: R
authors.lastname: Hilgenfeld
authors.forename: Ruihan
authors.initials: R
authors.lastname: Zhang
authors.forename: Xiangqian
authors.initials: X
authors.lastname: Kong
authors.forename: Lianchun
authors.initials: L
authors.lastname: Li
authors.forename: Junyan
authors.initials: J
authors.lastname: Lu
authors.forename: Xinlei
authors.initials: X
authors.lastname: Zhang
authors.forename: Donghai
authors.initials: D
authors.lastname: Li
authors.forename: Hualiang
authors.initials: H
authors.lastname: Jiang
authors.forename: Cai-Guang
authors.initials: CG
authors.lastname: Yang
authors.forename: Cheng
authors.initials: C
authors.lastname: Luo
mesh_terms: D019943:Amino Acid Substitution; D001426:Bacterial Proteins / Q000737:chemistry* / Q000235:genetics; D018360:Crystallography, X-Ray; D049071:Endopeptidase Clp / Q000737:chemistry* / Q000235:genetics; D004795:Enzyme Stability; D006860:Hydrogen Bonding; D056004:Molecular Dynamics Simulation; D025341:Principal Component Analysis; D058849:Protein Refolding; D020836:Protein Structure, Quaternary; D017433:Protein Structure, Secondary; D058767:Protein Unfolding; D013211:Staphylococcus aureus / Q000201:enzymology*; D013816:Thermodynamics
chemical_list: D001426:Bacterial Proteins; D049071:Endopeptidase Clp
keywords: Bacterial Pathogenesis; Clp Protease; Computational Biology; Crystal Structure; Energy Landscape; Molecular Dynamics; Principle-Component Analysis; Protein Dynamics