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Proc Natl Acad Sci U S A. 2016 Aug 23;113(34):9515-20. doi: 10.1073/pnas.1606160113. Epub 2016 Aug 10.

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

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  • 1Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA 92093;
  • 2Department of Pediatrics, University of California, San Diego, La Jolla, CA 92093;
  • 3Department of Pediatrics, University of California, San Diego, La Jolla, CA 92093; Skaggs School of Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA 92093.
  • 4Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA 92093; pghosh@ucsd.edu.

Abstract

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.

KEYWORDS:

M protein; coiled coil; dynamics; fibrinogen; group A Streptococcus

PMID:
27512043
PMCID:
PMC5003295
[Available on 2017-02-23]
DOI:
10.1073/pnas.1606160113
[PubMed - in process]
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