Dataset Information

Conserved patterns hidden within group A Streptococcus M protein hypervariability recognize human C4b-binding protein.

ABSTRACT: No vaccine exists against group A Streptococcus (GAS), a leading cause of worldwide morbidity and mortality. A severe hurdle is the hypervariability of its major antigen, the M protein, with >200 different M types known. Neutralizing antibodies typically recognize M protein hypervariable regions (HVRs) and confer narrow protection. In stark contrast, human C4b-binding protein (C4BP), which is recruited to the GAS surface to block phagocytic killing, interacts with a remarkably large number of M protein HVRs (apparently ?90%). Such broad recognition is rare, and we discovered a unique mechanism for this through the structure determination of four sequence-diverse M proteins in complexes with C4BP. The structures revealed a uniform and tolerant 'reading head' in C4BP, which detected conserved sequence patterns hidden within hypervariability. Our results open up possibilities for rational therapies that target the M-C4BP interaction, and also inform a path towards vaccine design.

SUBMITTER: Buffalo CZ

PROVIDER: S-EPMC5014329 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Conserved patterns hidden within group A Streptococcus M protein hypervariability recognize human C4b-binding protein.

Buffalo Cosmo Z CZ Bahn-Suh Adrian J AJ Hirakis Sophia P SP Biswas Tapan T Amaro Rommie E RE Nizet Victor V Ghosh Partho P

Nature microbiology 20160905 11

No vaccine exists against group A Streptococcus (GAS), a leading cause of worldwide morbidity and mortality. A severe hurdle is the hypervariability of its major antigen, the M protein, with >200 different M types known. Neutralizing antibodies typically recognize M protein hypervariable regions (HVRs) and confer narrow protection. In stark contrast, human C4b-binding protein (C4BP), which is recruited to the GAS surface to block phagocytic killing, interacts with a remarkably large number of M ...[more]

PMID: 27595425

Similar Datasets

Project description:Three vancomycin-resistant streptococcal strains carrying vanG elements (two invasive Streptococcus agalactiae isolates [GBS-NY and GBS-NM, both serotype II and multilocus sequence type 22] and one Streptococcus anginosus [Sa]) were examined. The 45,585-bp elements found within Sa and GBS-NY were nearly identical (together designated vanG-1) and shared near-identity over an ~15-kb overlap with a previously described vanG element from Enterococcus faecalis. Unexpectedly, vanG-1 shared much less homology with the 49,321-bp vanG-2 element from GBS-NM, with widely different levels (50% to 99%) of sequence identity shared among 44 related open reading frames. Immediately adjacent to both vanG-1 and vanG-2 were 44,670-bp and 44,680-bp integrative conjugative element (ICE)-like sequences, designated ICE-r, that were nearly identical in the two group B streptococcal (GBS) strains. The dual vanG and ICE-r elements from both GBS strains were inserted at the same position, between bases 1328 and 1329, within the identical RNA methyltransferase (rumA) genes. A GenBank search revealed that although most GBS strains contained insertions within this specific site, only sequence type 22 (ST22) GBS strains contained highly related ICE-r derivatives. The vanG-1 element in Sa was also inserted within this position corresponding to its rumA homolog adjacent to an ICE-r derivative. vanG-1 insertions were previously reported within the same relative position in the E. faecalis rumA homolog. An ICE-r sequence perfectly conserved with respect to its counterpart in GBS-NY was apparent within the same site of the rumA homolog of a Streptococcus dysgalactiae subsp. equisimilis strain. Additionally, homologous vanG-like elements within the conserved rumA target site were evident in Roseburia intestinalis. Importance: These three streptococcal strains represent the first known vancomycin-resistant strains of their species. The collective observations made from these strains reveal a specific hot spot for insertional elements that is conserved between streptococci and different Gram-positive species. The two GBS strains potentially represent a GBS lineage that is predisposed to insertion of vanG elements.

Project description:Experimental high-throughput studies of protein-protein interactions are beginning to provide enough data for comprehensive computational studies. Today, about ten large data sets, each with thousands of interacting pairs, coarsely sample the interactions in fly, human, worm, and yeast. Another about 55,000 pairs of interacting proteins have been identified by more careful, detailed biochemical experiments. Most interactions are experimentally observed in prokaryotes and simple eukaryotes; very few interactions are observed in higher eukaryotes such as mammals. It is commonly assumed that pathways in mammals can be inferred through homology to model organisms, e.g. the experimental observation that two yeast proteins interact is transferred to infer that the two corresponding proteins in human also interact. Two pairs for which the interaction is conserved are often described as interologs. The goal of this investigation was a large-scale comprehensive analysis of such inferences, i.e. of the evolutionary conservation of interologs. Here, we introduced a novel score for measuring the overlap between protein-protein interaction data sets. This measure appeared to reflect the overall quality of the data and was the basis for our two surprising results from our large-scale analysis. Firstly, homology-based inferences of physical protein-protein interactions appeared far less successful than expected. In fact, such inferences were accurate only for extremely high levels of sequence similarity. Secondly, and most surprisingly, the identification of interacting partners through sequence similarity was significantly more reliable for protein pairs within the same organism than for pairs between species. Our analysis underlined that the discrepancies between different datasets are large, even when using the same type of experiment on the same organism. This reality considerably constrains the power of homology-based transfer of interactions. In particular, the experimental probing of interactions in distant model organisms has to be undertaken with some caution. More comprehensive images of protein-protein networks will require the combination of many high-throughput methods, including in silico inferences and predictions. http://www.rostlab.org/results/2006/ppi_homology/

Dataset Information

Conserved patterns hidden within group A Streptococcus M protein hypervariability recognize human C4b-binding protein.

Publications

Conserved patterns hidden within group A Streptococcus M protein hypervariability recognize human C4b-binding protein.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets