Streptococcal M1 protein constructs a pathological host fibrinogen network

Machebœuf, Pauline; Buffalo, Cosmo Z.; Fu, Chiyu; Zinkernagel, Annelies S.; Cole, Jason N.; Johnson, John E.; Nizet, Victor; Ghosh, Partho

doi:10.1038/nature09967

Cited by 104 publications

(134 citation statements)

References 41 publications

Supporting

Mentioning

124

Contrasting

Unclassified

Order By: Relevance

“…Our work leads to the general conclusion that destabilizing residues are conserved through evolution in M proteins to enable functional interactions that are necessary for pathogenesis. (8). Register 2 was observed in the crystal structure of Fg-bound M1, in which the B repeats form a structurally canonical dimeric parallel coiled coil (8).…”

mentioning

confidence: 98%

“…(8). Register 2 was observed in the crystal structure of Fg-bound M1, in which the B repeats form a structurally canonical dimeric parallel coiled coil (8). Coiled-coil destabilizing residues occur with near equal frequency in registers 1 and 2, suggesting that the unbound form of register 2 is also likely to have an irregular conformation.…”

mentioning

confidence: 98%

“…1). For dimeric α-helical coiled coils, as is the case for M proteins (7)(8)(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.…”

mentioning

confidence: 99%

“…To address why M proteins have a high proportion of coiledcoil destabilizing residues, we investigated the M1 protein, which is the most structurally characterized M protein (8,9). M1 serotype strains are globally prevalent and are the leading single cause of severe invasive GAS disease (13).…”

mentioning

confidence: 99%

See 3 more Smart Citations

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.

Self Cite

View full text Add to dashboard Cite

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...

show abstract

mentioning

confidence: 98%

mentioning

confidence: 98%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

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.

Self Cite

View full text Add to dashboard Cite

show abstract

“…The majority of these models were created using highresolution data such as NMR or X-ray crystallography, but these datasets remain challenging to produce. One of the key surface proteins of S. pyogenes is the M protein, a coiled-coil homodimer that extends over 500 A from the cell wall; the M protein is thought to bind several plasma proteins such as fibrinogen [4] and albumin [5]. The crystal structure of M and fibrinogen was published in 2011, and the authors postulate that the M and fibrinogen form a complex structure on the surface of the bacterium.…”

Section: Introductionmentioning

confidence: 99%

Greedy motif-based approach to parsing large and diverge coiled-coil proteins into domains

Khakzad

Malmström

2017

Preprint

View full text Add to dashboard Cite

Bacterial surfaces are complex, built of from membranes, peptide-glycans and, importantly, proteins. The proteins play crucial roles as the key regulator of how the bacterium interacts with its environment. A full catalog of the motifs in coiled-coil proteins and their relative conservation grade is a pre-requisite to target the protein-protein interaction that bacterial surface protein makes to host proteins. Here, we present a greedy approach to iteratively identify conserved motifs in large sequence collections, identify all occurrences of these motifs and mask them. Remaining unmasked sequences are subjected to the second round of motif detection until no more significant motifs can be found or all protein segments have been assigned to a motif. We present the results for the S. pyogenes M protein. Given the speed and flexibility of our approach, we believe it will be useful in breaking analyzing surface protein of pathogens as these proteins are under high selective pressure and therefore cannot be analyzed using more traditional approaches such as multiple-sequence alignments. Preliminary data indicates that many of the newly discovered motifs are not always present together with adjacent motifs, indicating that they might have different and independent functions.

show abstract

Analysis of Bacterial Surface Interactions with Mass Spectrometry-Based Proteomics

Karlsson¹,

Teleman²,

Malmström³

2016

Methods in Molecular Biology

View full text Add to dashboard Cite

Host-pathogen protein-protein interaction networks are highly complex and dynamic. In this experimental protocol we describe a method to isolate host proteins attached to the bacterial surface followed by quantitative mass spectrometry based proteomics analysis. This technique provides an overview of the host-pathogen interaction network, which can be used to guide directed perturbations of the system, and to select target of specific interest for further studies.

show abstract

Streptococcal M1 protein constructs a pathological host fibrinogen network

Cited by 104 publications

References 41 publications

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

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

Greedy motif-based approach to parsing large and diverge coiled-coil proteins into domains

Analysis of Bacterial Surface Interactions with Mass Spectrometry-Based Proteomics

Contact Info

Product

Resources

About