Large-scale modelling as a route to multiple surface comparisons of the CCP module family

Soares, Dinesh C.; Gerloff, Dietlind L.; Syme, Neil; Coulson, Andrew; Parkinson, John; Barlow, Paul N.

doi:10.1093/protein/gzi039

Cited by 44 publications

(56 citation statements)

References 68 publications

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“…MBL/L-ficolin binding likely involves major ionic interactions between conserved lysine residues of their collagen stalks and surface-exposed acidic residues located in CR1 CCP24 and/or CCP25, which remain to be identified. Polymorphisms resulting in substitution of charged residues like some of the Knops blood groups might result in changes in the surface electrostatic properties of CCP modules and impair electrostatic interactions involving these residues or their close vicinity (69).…”

Section: Discussionmentioning

confidence: 99%

Deciphering Complement Receptor Type 1 Interactions with Recognition Proteins of the Lectin Complement Pathway

Jacquet

Lacroix²,

Ancelet³

et al. 2013

The Journal of Immunology

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Complement receptor type 1 (CR1) is a membrane receptor expressed on a wide range of cells. It is involved in immune complex clearance, phagocytosis, and complement regulation. Its ectodomain is composed of 30 complement control protein (CCP) modules, organized into four long homologous repeats (A–D). In addition to its main ligands C3b and C4b, CR1 was reported to interact with C1q and mannan-binding lectin (MBL) likely through its C-terminal region (CCP22–30). To decipher the interaction of human CR1 with the recognition proteins of the lectin complement pathway, a recombinant fragment encompassing CCP22–30 was expressed in eukaryotic cells, and its interaction with human MBL and ficolins was investigated using surface plasmon resonance spectroscopy. MBL and L-ficolin were shown to interact with immobilized soluble CR1 and CR1 CCP22–30 with apparent dissociation constants in the nanomolar range, indicative of high affinity. The binding site for CR1 was located at or near the MBL-associated serine protease (MASP) binding site in the collagen stalks of MBL and L-ficolin, as shown by competition experiments with MASP-3. Accordingly, the mutation of an MBL conserved lysine residue essential for MASP binding (K55) abolished binding to soluble CR1 and CCP22–30. The CR1 binding site for MBL/ficolins was mapped to CCP24–25 of long homologous repeat D using deletion mutants. In conclusion, we show that ficolins are new CR1 ligands and propose that MBL/L-ficolin binding involves major ionic interactions between conserved lysine residues of their collagen stalks and surface exposed acidic residues located in CR1 CCP24 and/or CCP25.

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Section: Discussionmentioning

confidence: 99%

Deciphering Complement Receptor Type 1 Interactions with Recognition Proteins of the Lectin Complement Pathway

Jacquet

Lacroix²,

Ancelet³

et al. 2013

The Journal of Immunology

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“…The presence of such a loop, four mostly polar residues bounded by two hydrophobic residues that can contribute to the interface with the preceding module, is unique to cluster C CCP modules (40). Since cluster C members form the second modules of C3b/C4b recognition sites in C4BP, MCP, DAF, and both sites 1 and 2 of CR1, some conservation among these modules in the use of specific features for C3b/C4b binding might be expected.…”

Section: Discussionmentioning

confidence: 99%

Human C4b-binding Protein, Structural Basis for Interaction with Streptococcal M Protein, a Major Bacterial Virulence Factor

Jenkins

Mark

Ball

et al. 2006

Journal of Biological Chemistry

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Human C4b-binding protein (C4BP) protects host tissue, and those pathogens able to hijack this plasma glycoprotein, from complement-mediated destruction. We now show that the first two complement control protein (CCP) modules of the C4BP ␣-chain, plus the four residues connecting them, are necessary and sufficient for binding a bacterial virulence factor, the Streptococcus pyogenes M4 (Arp4) protein. Structure determination by NMR reveals two tightly coupled CCP modules in an elongated arrangement within this region of C4BP. Chemical shift perturbation studies demonstrate that the N-terminal, hypervariable region of M4 binds to a site including strand 1 of CCP module 2. This interaction is accompanied by an intermodular reorientation within C4BP. We thus provide a detailed picture of an interaction whereby a pathogen evades complement.Bacteria that enter human blood or tissues will be opsonized by complement and destroyed by phagocytes unless they have a means of overcoming attack by the complement system. An extensively studied example of such a virulence mechanism is the ability of many Streptococcus pyogenes M proteins to bind the key human complement regulator C4b-binding protein (C4BP), 2 an interaction that endows the bacteria with resistance to phagocytosis (1). C4BP is a polymeric, soluble, glycoprotein (ϳ200 mg/liter in plasma) (2). The M proteins, classical bacterial virulence factors first recognized over 75 years ago (3), are fibrillar surface structures exhibiting antigenic variation within a 50 -100-amino acid residue hypervariable N terminus (4, 5). Expression of M protein is important for the ability of S. pyogenes to cause the diseases associated with this pathogen: acute pharyngitis and impetigo (6). Many other pathogens share the ability to sequester C4BP (7-12). Thus escape from complement attack by hijacking of C4BP is emerging as a widespread contributor to immune evasion strategies and is a therapeutic target.The complement system, a vital molecular component of innate immunity, consists of plasma and cell-surface proteins that conspire to rid the body of infectious particles (13,14). Because complement is potentially harmful to host tissue it is tightly regulated. Like other members of the regulators of complement activation (RCA) protein family, the plasma protein C4BP acts upon the bimolecular C3 convertases that are the main drivers of the complement cascade. The C3 convertases cleave and thereby activate the third component of complement, C3, leading to deposition of C3b on the surface of an unprotected particle such as an invading microorganism. This process, known as opsonization, marks the particle as a target for phagocytosis. C3b also nucleates assembly of further convertase complexes and progression of the cascade toward formation of the membrane attack complex. C4BP regulates the C3 convertase of the classical pathway, a complex of C4b and C2a, by acting as a cofactor for the proteolysis of C4b (15, 16) and accelerating the decay of C4b⅐C2a complexes deposited on host cells (17...

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“…While the invariant four cysteines were present in the apicomplexan sequences, the parasite domains substitute the highly conserved tryptophan located near the C terminus, with a tyrosine or phenylalanine. Phylogenetic reconstruction of this domain has previously proven difficult (Soares et al 2005), so to investigate relationships between the sequences, all-against-all pairwise alignments were generated, and the scores were hierarchically clustered. The parasite sequences were placed in a clade with domains from regulators of complement activity (RCA) proteins, including C4b-binding protein and complement receptor type 1 (Supplemental Fig.…”

Section: Expanding the Repertoire Of Protein Domains To The Apicomplexamentioning

confidence: 99%

The origins of apicomplexan sequence innovation

Wasmuth¹,

Daub²,

Peregrín-Alvarez³

et al. 2009

Genome Res.

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The Apicomplexa are a group of phylogenetically related parasitic protists that include Plasmodium, Cryptosporidium, and Toxoplasma. Together they are a major global burden on human health and economics. To meet this challenge, several international consortia have generated vast amounts of sequence data for many of these parasites. Here, we exploit these data to perform a systematic analysis of protein family and domain incidence across the phylum. A total of 87,736 protein sequences were collected from 15 apicomplexan species. These were compared with three protein databases, including the partial genome database, PartiGeneDB, which increases the breadth of taxonomic coverage. From these searches we constructed taxonomic profiles that reveal the extent of apicomplexan sequence diversity. Sequences without a significant match outside the phylum were denoted as apicomplexan specialized. These were collated into 9134 discrete protein families and placed in the context of the apicomplexan phylogeny, identifying the putative origin of each family. Most apicomplexan families were associated with an individual genus or species. Interestingly, many genera-specific innovations were associated with specialized host cell invasion and/or parasite survival processes. Contrastingly, those families reflecting more ancestral relationships were enriched in generalized housekeeping functions such as translation and transcription, which have diverged within the apicomplexan lineage. Protein domain searches revealed 192 domains not previously reported in apicomplexans together with a number of novel domain combinations. We highlight domains that may be important to parasite survival.

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Large-scale modelling as a route to multiple surface comparisons of the CCP module family

Cited by 44 publications

References 68 publications

Deciphering Complement Receptor Type 1 Interactions with Recognition Proteins of the Lectin Complement Pathway

Deciphering Complement Receptor Type 1 Interactions with Recognition Proteins of the Lectin Complement Pathway

Human C4b-binding Protein, Structural Basis for Interaction with Streptococcal M Protein, a Major Bacterial Virulence Factor

The origins of apicomplexan sequence innovation

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