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The HAMP signal relay domain adopts multiple conformational states through collective piston and tilt motions.

Zhu L, Bolhuis PG, Vreede J - PLoS Comput. Biol. (2013)

Bottom Line: These simulations revealed additional conformational states that differ in the tilt angles between the helices as well as the relative piston shifts of the helices relative to each other.Our results indicate that HAMP can access additional conformational states characterized by piston motion.Our results provide insights into the conformational changes that underlie the signaling mechanism involving HAMP.

View Article: PubMed Central - PubMed

Affiliation: Van 't Hoff Institute for Molecular Sciences, University of Amsterdam, Amsterdam, The Netherlands.

ABSTRACT
The HAMP domain is a linker region in prokaryotic sensor proteins and relays input signals to the transmitter domain and vice versa. Functional as a dimer, the structure of HAMP shows a parallel coiled-coil motif comprising four helices. To date, it is unclear how HAMP can relay signals from one domain to another, although several models exist. In this work, we use molecular simulation to test the hypothesis that HAMP adopts different conformations, one of which represents an active, signal-relaying configuration, and another an inactive, resting state. We first performed molecular dynamics simulation on the prototype HAMP domain Af1503 from Archaeoglobus fulgidus. We explored its conformational space by taking the structure of the A291F mutant disabling HAMP activity as a starting point. These simulations revealed additional conformational states that differ in the tilt angles between the helices as well as the relative piston shifts of the helices relative to each other. By enhancing the sampling in a metadynamics set up, we investigated three mechanistic models for HAMP signal transduction. Our results indicate that HAMP can access additional conformational states characterized by piston motion. Furthermore, the piston motion of the N-terminal helix of one monomer is directly correlated with the opposite piston motion of the C-terminal helix of the other monomer. The change in piston motion is accompanied by a change in tilt angle between the monomers, thus revealing that HAMP exhibits a collective motion, i.e. a combination of changes in tilt angles and a piston-like displacement. Our results provide insights into the conformational changes that underlie the signaling mechanism involving HAMP.

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Deviation of the ideal Crick angles for the four piston states.The Crick angle deviation is plotted as a function of residue in the N and C-helices for the , ,  and  states. The error bars indicate the variation over 40 snapshots. The dashed lines represent the Crick angle deviations as measured for the NMR structure of wild-type Af1503-HAMP (PDB-code 2L7I). There are little differences between the states.
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pcbi-1002913-g007: Deviation of the ideal Crick angles for the four piston states.The Crick angle deviation is plotted as a function of residue in the N and C-helices for the , , and states. The error bars indicate the variation over 40 snapshots. The dashed lines represent the Crick angle deviations as measured for the NMR structure of wild-type Af1503-HAMP (PDB-code 2L7I). There are little differences between the states.

Mentions: The role of helical rotation is less clear, as our results seem to indicate that changes in rotation occur independently with respect to changes in the piston shifts or tilt angles. Directly biasing the rotation angle results in small changes of the other rotation angles, but not in visiting an additional conformational state. As we calculated the rotation as a single value for an entire helix, we cannot directly compare our results with the gearbox model. To this end, we extracted 40 snapshots from each piston-shifted state and computed several properties related to four-helical bundles for each residue, using the SamCC software [4], [7]. One of these properties is the Crick angle per residue, measured as the angle between the center of the bundle, the -atom of the residue and the point on the principal axis of the helix closest to the residue. The Crick angles are known for an ideal helical bundle, so we can also measure the deviation from the ideal packing. In FIG. 7 we show the deviation from the ideal Crick angle for all four piston states. In all states the overall deviation is close to for the N-helices and for the C-helices and does not come close to zero in any of the states. The curves representing the helices in the state are very similar to the curve measured for the NMR structure of wild-type Af1503-HAMP (dashed lines). The four states exhibit small differences in the Crick angle deviation, as indicated by the arrows.


The HAMP signal relay domain adopts multiple conformational states through collective piston and tilt motions.

Zhu L, Bolhuis PG, Vreede J - PLoS Comput. Biol. (2013)

Deviation of the ideal Crick angles for the four piston states.The Crick angle deviation is plotted as a function of residue in the N and C-helices for the , ,  and  states. The error bars indicate the variation over 40 snapshots. The dashed lines represent the Crick angle deviations as measured for the NMR structure of wild-type Af1503-HAMP (PDB-code 2L7I). There are little differences between the states.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3585426&req=5

pcbi-1002913-g007: Deviation of the ideal Crick angles for the four piston states.The Crick angle deviation is plotted as a function of residue in the N and C-helices for the , , and states. The error bars indicate the variation over 40 snapshots. The dashed lines represent the Crick angle deviations as measured for the NMR structure of wild-type Af1503-HAMP (PDB-code 2L7I). There are little differences between the states.
Mentions: The role of helical rotation is less clear, as our results seem to indicate that changes in rotation occur independently with respect to changes in the piston shifts or tilt angles. Directly biasing the rotation angle results in small changes of the other rotation angles, but not in visiting an additional conformational state. As we calculated the rotation as a single value for an entire helix, we cannot directly compare our results with the gearbox model. To this end, we extracted 40 snapshots from each piston-shifted state and computed several properties related to four-helical bundles for each residue, using the SamCC software [4], [7]. One of these properties is the Crick angle per residue, measured as the angle between the center of the bundle, the -atom of the residue and the point on the principal axis of the helix closest to the residue. The Crick angles are known for an ideal helical bundle, so we can also measure the deviation from the ideal packing. In FIG. 7 we show the deviation from the ideal Crick angle for all four piston states. In all states the overall deviation is close to for the N-helices and for the C-helices and does not come close to zero in any of the states. The curves representing the helices in the state are very similar to the curve measured for the NMR structure of wild-type Af1503-HAMP (dashed lines). The four states exhibit small differences in the Crick angle deviation, as indicated by the arrows.

Bottom Line: These simulations revealed additional conformational states that differ in the tilt angles between the helices as well as the relative piston shifts of the helices relative to each other.Our results indicate that HAMP can access additional conformational states characterized by piston motion.Our results provide insights into the conformational changes that underlie the signaling mechanism involving HAMP.

View Article: PubMed Central - PubMed

Affiliation: Van 't Hoff Institute for Molecular Sciences, University of Amsterdam, Amsterdam, The Netherlands.

ABSTRACT
The HAMP domain is a linker region in prokaryotic sensor proteins and relays input signals to the transmitter domain and vice versa. Functional as a dimer, the structure of HAMP shows a parallel coiled-coil motif comprising four helices. To date, it is unclear how HAMP can relay signals from one domain to another, although several models exist. In this work, we use molecular simulation to test the hypothesis that HAMP adopts different conformations, one of which represents an active, signal-relaying configuration, and another an inactive, resting state. We first performed molecular dynamics simulation on the prototype HAMP domain Af1503 from Archaeoglobus fulgidus. We explored its conformational space by taking the structure of the A291F mutant disabling HAMP activity as a starting point. These simulations revealed additional conformational states that differ in the tilt angles between the helices as well as the relative piston shifts of the helices relative to each other. By enhancing the sampling in a metadynamics set up, we investigated three mechanistic models for HAMP signal transduction. Our results indicate that HAMP can access additional conformational states characterized by piston motion. Furthermore, the piston motion of the N-terminal helix of one monomer is directly correlated with the opposite piston motion of the C-terminal helix of the other monomer. The change in piston motion is accompanied by a change in tilt angle between the monomers, thus revealing that HAMP exhibits a collective motion, i.e. a combination of changes in tilt angles and a piston-like displacement. Our results provide insights into the conformational changes that underlie the signaling mechanism involving HAMP.

Show MeSH