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Coiled-coil response to mechanical force: global stability and local cracking.

ABSTRACT: Coiled coils are important structural motifs formed by two or more amphipathic ?-helices that twist into a supercoil. These motifs are found in a wide range of proteins, including motor proteins and structural proteins, that are known to transmit mechanical loads. We analyze atomically detailed simulations of coiled-coil cracking under load with Milestoning. Milestoning is an approach that captures the main features of the process in a network, quantifying kinetics and thermodynamics. A 112-residue segment of the ?-myosin S2 domain was subjected to constant-magnitude (0-200 pN) and constant-direction tensile forces in molecular dynamics simulations. Twenty 20 ns straightforward simulations at several load levels revealed that initial single-residue cracking events (? > 90°) at loads <100 pN were accompanied by rapid refolding without either intra- or interhelix unfolding propagation. Only initial unfolding events at the highest load (200 pN) regularly propagated along and between helices. Analysis of hydrophobic interactions and of interhelix hydrogen bonds did not show significant variation as a function of load. Unfolding events were overwhelmingly located in the vicinity of E929, a charged residue in a hydrophobic position of the heptad repeat. Milestoning network analysis of E929 cracking determined that the mean first-passage time ranges from 20 ns (200 pN) to 80 ns (50 pN), which is ?20 times the mean first-passage time of an isolated helix with the same sequence.

SUBMITTER: Kreuzer SM

PROVIDER: S-EPMC3752098 | biostudies-literature | 2013 Aug

REPOSITORIES: biostudies-literature

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Coiled-coil response to mechanical force: global stability and local cracking.

Kreuzer Steven M SM Elber Ron R

Biophysical journal 20130801 4

Coiled coils are important structural motifs formed by two or more amphipathic α-helices that twist into a supercoil. These motifs are found in a wide range of proteins, including motor proteins and structural proteins, that are known to transmit mechanical loads. We analyze atomically detailed simulations of coiled-coil cracking under load with Milestoning. Milestoning is an approach that captures the main features of the process in a network, quantifying kinetics and thermodynamics. A 112-resi ...[more]

PMID: 23972847

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Project description:UnlabelledThe two-component system BvgAS controls the expression of the virulence regulon of Bordetella pertussis. BvgS is a prototype of bacterial sensor kinases with extracytoplasmic Venus flytrap perception domains. Following its transmembrane segment, BvgS harbors a cytoplasmic Per-Arnt-Sim (PAS) domain and then a predicted 2-helix coiled coil that precede the dimerization-histidine-phosphotransfer domain of the kinase. BvgS homologs have a similar domain organization, or they harbor only a predicted coiled coil between the transmembrane and the dimerization-histidine-phosphotransfer domains. Here, we show that the 2-helix coiled coil of BvgS regulates the enzymatic activity in a mechanical manner. Its marginally stable hydrophobic interface enables a switch between a state of great rotational dynamics in the kinase mode and a more rigid conformation in the phosphatase mode in response to signal perception by the periplasmic domains. We further show that the activity of BvgS is controlled in the same manner if its PAS domain is replaced with the natural α-helical sequences of PAS-less homologs. Clamshell motions of the Venus flytrap domains trigger the shift of the coiled coil's dynamics. Thus, we have uncovered a general mechanism of regulation for the BvgS family of Venus flytrap-containing two-component sensor kinases.ImportanceThe two-component system BvgAS of the whooping cough agent Bordetella pertussis regulates the virulence factors necessary for infection in a coordinated manner. BvgS is the prototype of a family of sensor kinase proteins found in major bacterial pathogens. When BvgS functions as a kinase, B. pertussis is virulent, and the bacterium shifts to an avirulent phase after BvgS senses chemicals that make it switch to phosphatase. Our goal is to decipher the signaling mechanisms of BvgS in order to understand virulence regulation in Bordetella, which may lead to new antimicrobial treatments targeting those two-component systems. We discovered that the activity of BvgS is regulated in a mechanical manner. A short region of the protein that precedes the enzymatic domain switches between two states in response to signal perception by other BvgS domains. This switch region is conserved among BvgS homologs, and thus, the regulation uncovered here will likely be relevant for the family.

Dataset Information

Coiled-coil response to mechanical force: global stability and local cracking.

Publications

Coiled-coil response to mechanical force: global stability and local cracking.

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