title: Force distribution reveals signal transduction in E. coli Hsp90.
abstract: Heat-shock protein 90 (Hsp90) is an ubiquitous chaperone that is essential for cell function in that it promotes client-protein folding and stabilization. Its function is tightly controlled by an ATP-dependent large conformational transition between the open and closed states of the Hsp90 dimer. The underlying allosteric pathway has remained largely unknown, but it is revealed here in atomistic detail for the Escherichia coli homolog HtpG. Using force-distribution analysis based on molecular-dynamics simulations (>1 μs in total), we identify an internal signaling pathway that spans from the nucleotide-binding site to an ~2.3-nm-distant region in the HtpG middle domain, that serves as a dynamic hinge region, and to a putative client-protein-binding site in the middle domain. The force transmission is triggered by ATP capturing a magnesium ion and thereby rotating and bending a proximal long α-helix, which represents the major force channel into the middle domain. This allosteric mechanism is, with statistical significance, distinct from the dynamics in the ADP and apo states. Tracking the distribution of forces is likely to be a promising tool for understanding and guiding experiments of complex allosteric proteins in general.
authors.affiliation: Molecular Biomechanics, Heidelberger Institut für Theoretische Studien gGmbH, Heidelberg, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Seifert
authors.forename: Frauke
authors.initials: F
authors.lastname: Gräter
mesh_terms: D001696:Biomechanical Phenomena; D004926:Escherichia coli / Q000378:metabolism*; D029968:Escherichia coli Proteins / Q000737:chemistry / Q000378:metabolism*; D018841:HSP90 Heat-Shock Proteins / Q000737:chemistry / Q000378:metabolism*; D008954:Models, Biological; D009711:Nucleotides / Q000378:metabolism; D011485:Protein Binding; D011487:Protein Conformation; D055503:Protein Multimerization; D015398:Signal Transduction
chemical_list: D029968:Escherichia coli Proteins; D018841:HSP90 Heat-Shock Proteins; C489352:HtpG protein, E coli; D009711:Nucleotides