The Mechanisms of HAMP-Mediated Signaling in Transmembrane Receptors

Ferris, Hedda U.; Dunin-Horkawicz, Stanisław; Mondéjar, Laura García; Hulko, Michael; Hantke, Klaus; Martin, Jörg; Schultz, Joachim E.; Zeth, Kornelius; Lupas, Andrei N.; Coles, Murray

doi:10.1016/j.str.2011.01.006

Cited by 88 publications

(133 citation statements)

References 22 publications

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“…Consistent with a transition between different packing modes, when the volume of a conserved small side chain at a core position (Ala-291 in Af1503 HAMP) was increased by point mutations, the maximal catalytic velocity of the HAMP-CHD chimera decreased (6). Structurally, we recently demonstrated that such substitutions induce a gradual transition in packing of the HAMP domain involving both changes in helix rotation toward a knobs-into-holes packing and changes in bundle shape, consistent with the proposed two-state model (16).…”

supporting

confidence: 81%

“…Serine regulation was achieved by substitution of Ala-291 with Phe, supporting the notion of rotation as a potentially common mechanism in HAMP-mediated signal propagation (16). Here we used this Tsr-AC reporter system with the Tsr or Af1503 HAMP domains and carried out a targeted mutational analysis based on sequence and structural features to investigate the role of particular amino acids in signal propagation.…”

mentioning

confidence: 83%

“…Although it was an attractive idea to join the Tsr receptor to the Rv3645 CHD via the structurally defined Af1503 HAMP, such a tripartite chimera was unresponsive to serine (16). Serine regulation was achieved by substitution of Ala-291 with Phe, supporting the notion of rotation as a potentially common mechanism in HAMP-mediated signal propagation (16).…”

mentioning

confidence: 99%

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HAMP Domain-mediated Signal Transduction Probed with a Mycobacterial Adenylyl Cyclase as a Reporter

Mondéjar

Lupas

Schultz

et al. 2012

Journal of Biological Chemistry

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Background: HAMP domains accept signals from membrane receptors and propagate them possibly via rotation. Results: Using targeted mutations based on bioinformatics, sequence comparisons, and structures, we characterize the role of particular amino acids in signaling. Conclusion: Results are compatible with a gearbox model of HAMP rotation. Significance: Various models of HAMP domain-mediated signaling are testable.

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confidence: 81%

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confidence: 83%

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HAMP Domain-mediated Signal Transduction Probed with a Mycobacterial Adenylyl Cyclase as a Reporter

Mondéjar

Lupas

Schultz

et al. 2012

Journal of Biological Chemistry

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“…The authors speculated that the competing Nek2 registers may act as a "toggle" in signal transmission, analogous to the coiled coil in the HAMP domain of Af1503 and the microtubule-binding domain of dynein. In the former, a conformational shift in registers of a tetrameric coiled coil is necessary to transmit signals across a membrane (24,25), and in the latter, helix sliding in the dynein coiled coil is required for communication between the ATPase and microtubule binding domains of dynein (26,27). These toggle signaling mechanisms differ from the capture-and-collapse mechanism we propose for M1 protein.…”

Section: Discussionmentioning

confidence: 74%

Coiled-coil destabilizing residues in the group A Streptococcus M1 protein are required for functional interaction

Stewart

Buffalo

Valderrama

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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The sequences of M proteins, the major surface-associated virulence factors of the widespread bacterial pathogen group A Streptococcus, are antigenically variable but have in common a strong propensity to form coiled coils. Paradoxically, these sequences are also replete with coiled-coil destabilizing residues. These features are evident in the irregular coiled-coil structure and thermal instability of M proteins. We present an explanation for this paradox through studies of the B repeats of the medically important M1 protein. The B repeats are required for interaction of M1 with fibrinogen (Fg) and consequent proinflammatory activation. The B repeats sample multiple conformations, including intrinsically disordered, dissociated, as well as two alternate coiled-coil conformations: a Fg-nonbinding register 1 and a Fg-binding register 2. Stabilization of M1 in the Fg-nonbinding register 1 resulted in attenuation of Fg binding as expected, but counterintuitively, so did stabilization in the Fg-binding register 2. Strikingly, these register-stabilized M1 proteins gained the ability to bind Fg when they were destabilized by a chaotrope. These results indicate that M1 stability is antithetical to Fg interaction and that M1 conformational dynamics, as specified by destabilizing residues, are essential for interaction. A "capture-and-collapse" model of association accounts for these observations, in which M1 captures Fg through a dynamic conformation and then collapses into a register 2-coiled coil as a result of stabilization provided by binding energy. Our results support the general conclusion that destabilizing residues are evolutionarily conserved in M proteins to enable functional interactions necessary for pathogenesis.M proteins are the major surface-associated virulence factors of group A Streptococcus (GAS; Streptococcus pyogenes) and play a significant role in the diverse diseases caused by this widespread bacterial pathogen (1-3). M protein sequences are antigenically variable but have in common a strong propensity to form α-helical coiled coils (4). Paradoxically, these sequences are also replete with residues that destabilize coiled coils (5, 6). These destabilizing residues occur at the central a and d positions of the coiled-coil [abcdefg] n heptad repeat (Fig. 1). For dimeric α-helical coiled coils, as is the case for M proteins (7-9), the a and d positions are preferentially occupied by Val and Leu, respectively (10, 11). These small, hydrophobic residues typically engage in "knobs-into-hole" packing and form the hydrophobic core of the coiled-coil dimer. In contrast, the a and d positions of M proteins are often occupied by coiled-coil destabilizing residues (e.g., charged residues or alanines), and the heptad pattern sometimes contains short insertions or deletions (Fig. 1B) (5, 9). These sorts of destabilizing residues and heptad disruptions result in a highly irregular coiled-coil structure in M1 protein (9). The high proportion of coiled-coil destabilizing residues is also consistent with M protei...

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“…Attractant-sensitive disulfide bond formation between CheA and receptor suggests that the N-terminal CD1 helices rotate in the PIR on ligand binding (20). Rotations (21,22) and longitudinal shifts of helices (23) within HAMP have been implicated as regulatory switches, and such transitions may interconvert states with different dynamical properties. Long-duration, all-atom molecular dynamics simulations indicate that separations of one KCM N-terminal helix (CD1) and the C-terminal helix of the other subunit (CD2′) are coupled to the flipping of a conserved Phe residue at the receptor tip and that these changes correlate with modification state (24).…”

mentioning

confidence: 99%

Bacterial chemoreceptor dynamics correlate with activity state and are coupled over long distances

Samanta

Borbat

Dzikovski

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Dynamics are hypothesized to play an important role in the transmission of signals across membranes by receptors. Bacterial chemoreceptors are long helical proteins that consist of a periplasmic ligand-binding domain; a transmembrane region; a cytoplasmic HAMP (histidine kinase, adenylyl cyclases, methyl-accepting chemotaxis proteins, and phosphatases) domain; and a kinase-control module (KCM). The KCM is further composed of adaptation, hinge, and protein interaction regions (PIRs), the latter of which binds the histidine kinase CheA and adaptor CheW. Fusions of the Escherichia coli aspartate receptor KCM to HAMP domains of defined structure (H1-Tar vs. H1-2-Tar) give opposite responses in phosphotransfer and cellular assays, despite similar binding to CheA and CheW. Pulsed dipolar ESR spectroscopy (PDS) of these isolated on and off dimeric effectors reveals that, in the kinase-on state, the HAMP is more conformationally destabilized compared with the PIR, whereas in the kinase-off state, the HAMP is more compact, and the PIR samples a greater breadth of conformations. On and off HAMP states produce different conformational effects at the KCM junction, but these differences decrease through the adaptation region and into the hinge only to return with the inverted relationship in the PIR. Continuous wave-ESR of the spin-labeled proteins confirms that broader PDS distance distributions correlate with increased rates of dynamics. Conformational breadth in the adaptation region changes with charge alterations caused by modification enzymes. Activating modifications broaden the HAMP conformational ensemble but correspondingly, compact the PIR. Thus, chemoreceptors behave as coupled units, in which dynamics in regions proximal and distal to the membrane change coherently but with opposite sign.chemotaxis | transmembrane signaling receptor | allostery | dynamics | adaptation T he ability of localized dynamics to modulate the function of transmembrane receptors is an emerging theme in signal transduction (1-4). These ideas have been largely supported by computational studies (2), although direct measurements also correlate dynamics with activity (1-4). Nonetheless, we are only beginning to address the link between conformational heterogeneity and signal propagation in complex proteins. Bacterial chemotaxis, the process by which cells modulate their motility in response to the chemical environment, provides an important model system to explore receptor dynamics experimentally (5, 6). During chemotaxis, attractant-bound chemoreceptors cause counterclockwise (CCW) flagella rotation and smooth swimming, whereas repellant-bound receptors cause clockwise flagella rotation and cell tumbling. Chemoreceptors, also termed methyl-accepting chemotaxis proteins, form extended arrays in the cytoplasmic membrane to communicate ligand binding (6) to the histidine kinase CheA and the coupling protein CheW. Great progress has been made in understanding how receptors communicate ligand-binding events across the cytoplasmic membrane, but h...

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The Mechanisms of HAMP-Mediated Signaling in Transmembrane Receptors

Cited by 88 publications

References 22 publications

HAMP Domain-mediated Signal Transduction Probed with a Mycobacterial Adenylyl Cyclase as a Reporter

HAMP Domain-mediated Signal Transduction Probed with a Mycobacterial Adenylyl Cyclase as a Reporter

Coiled-coil destabilizing residues in the group A Streptococcus M1 protein are required for functional interaction

Bacterial chemoreceptor dynamics correlate with activity state and are coupled over long distances

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