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Richard William Farndale – One of the best experts on this subject based on the ideXlab platform.

  • an activating mutation reveals a second binding mode of the integrin α2 i domain to the gfoger motif in Collagens
    PLOS ONE, 2013
    Co-Authors: Federico Carafoli, Dominique Bihan, Samir W Hamaia, Erhard Hohenester, Richard William Farndale

    The GFOGER motif in Collagens (O denotes hydroxyproline) represents a high-affinity binding site for all Collagen-binding integrins. Other GxOGER motifs require integrin activation for maximal binding. The E318W mutant of the integrin α2β1 I domain displays a relaxed Collagen specificity, typical of an active state. E318W binds more strongly than the wild-type α2 I domain to GMOGER, and forms a 2:1 complex with a homotrimeric, Collagen-like, GFOGER peptide. Crystal structure analysis of this complex reveals two E318W I domains, A and B, bound to a single triple helix. The E318W I domains are virtually identical to the Collagen-bound wild-type I domain, suggesting that the E318W mutation activates the I domain by destabilising the unligated conformation. E318W I domain A interacts with two Collagen chains similarly to wild-type I domain (high-affinity mode). E318W I domain B makes favourable interactions with only one Collagen chain (low-affinity mode). This observation suggests that single GxOGER motifs in the heterotrimeric Collagens V and IX may support binding of activated integrins.

  • Collagen binding specificity of the discoidin domain receptors binding sites on Collagens ii and iii and molecular determinants for Collagen iv recognition by ddr1
    Matrix Biology, 2011
    Co-Authors: Huifang Xu, Johanna Myllyharju, Nicolas Raynal, Stavros Stathopoulos, Richard William Farndale, Birgit Leitinger

    The discoidin domain receptors, DDR1 and DDR2 are cell surfsurface receptor tyrosine kinases that are activated by triple-helical Collagen. While normal DDR signalling regulates fundamental cellular processes, aberrant DDR signalling is associated with several human diseases. We previously identified GVMGFO (O is hydroxyproline) as a major DDR2 binding site in Collagens I–III, and located two additional DDR2 binding sites in Collagen II. Here we extend these studies to the homologous DDR1 and the identification of DDR binding sites on Collagen III. Using sets of overlapping triple-helical peptides, the Collagen II and Collagen III Toolkits, we located several DDR2 binding sites on both Collagens. The interaction of DDR1 with Toolkit peptides was more restricted, with DDR1 mainly binding to peptides containing the GVMGFO motif. Triple-helical peptides containing the GVMGFO motif induced DDR1 transmembrane signalling, and DDR1 binding and receptor activation occurred with the same amino acid requirements as previously defined for DDR2. While both DDRs exhibit the same specificity for binding the GVMGFO motif, which is present only in fibrillar Collagens, the two receptors display distinct preferences for certain non-fibrillar Collagens, with the basement membrane Collagen IV being exclusively recognised by DDR1. Based on our recent crystal structure of a DDR2-Collagen complex, we designed mutations to identify the molecular determinants for DDR1 binding to Collagen IV. By replacing five amino acids in DDR2 with the corresponding DDR1 residues we were able to create a DDR2 construct that could function as a Collagen IV receptor.

  • first analysis of a bacterial Collagen binding protein with Collagen toolkits promiscuous binding of yada to Collagens may explain how yada interferes with host processes
    Infection and Immunity, 2010
    Co-Authors: Heli Elovaara, Nicolas Raynal, Richard William Farndale, Dominique Bihan, Nicholas Pugh, Sami K Kilpinen, Mikael Skurnik, Adrian Goldman

    The Yersinia adhesin YadA mediates the adhesion of the human enteropathogen Yersinia enterocolitica to Collagens and other components of the extracellular matrix. Though YadA has been proposed to bind to a specific site in Collagens, the exact binding determinants for YadA in native Collagen have not previously been elucidated. We investigated the binding of YadA to Collagen Toolkits, which are libraries of triple-helical peptides spanning the sequences of type II and III human Collagens. YadA bound to many of them, in particular to peptides rich in hydroxyproline but with few charged residues. We were able to block the binding of YadA to Collagen type IV with the triple-helical peptide (Pro-Hyp-Gly)10, suggesting that the same site in YadA binds to triple-helical regions in network-forming Collagens as well. We showed that a single Gly-Pro-Hyp triplet in a triple-helical peptide was sufficient to support YadA binding, but more than six triplets were required to form a tight YadA binding site. This is significantly longer than the case for eukaryotic Collagenbinding protproteins. YadA-expressing bacteria bound promiscuously to Toolkit peptides. Promiscuous binding could be advantageous for pathogenicity in Y. enterocolitica and, indeed, for other pathogenic bacteria. Many of the tightly binding peptides are also targets for eukaryotic Collagenbinding protproteins, and YadA was able to inhibit the interaction between selected Toolkit peptides and platelets. This leads to the intriguing possibility that YadA may interfere in vivo with host processes mediated by endogenous Collagenbinding protproteins.

Michael S Yu – One of the best experts on this subject based on the ideXlab platform.

  • targeting and mimicking Collagens via triple helical peptide assembly
    Current Opinion in Chemical Biology, 2013
    Co-Authors: Yang Li, Michael S Yu

    As the major structural component of the extracellular matrix, Collagen plays a crucial role in tissue development and regeneration. Since structural and metabolic abnormalities of Collagen are associated with numerous debilitating diseases and pathologic conditions, the ability to target Collagens of diseased tissues could lead to new diagnostics and therapeutics. Collagen is also a natural biomaterial widely used in drug delivery and tissue engineering, and construction of synthetic Collagen-like materials is gaining interests in the biomaterials community. The unique triple helical structure of Collagen has been explored for targeting Collagen strands, and for engineering Collagen-like functional assemblies and conjugates. This review focuses on the forefront of research activities in the use of the Collagen mimetic peptide for both targeting and mimicking Collagens via its triple helix mediated strand hybridization and higher order assembly.

John J. Robinson – One of the best experts on this subject based on the ideXlab platform.

John R Baker – One of the best experts on this subject based on the ideXlab platform.

  • isolation and characterization of the chains of type v type xi Collagen present in bovine vitreous
    Journal of Biological Chemistry, 1993
    Co-Authors: Richard Mayne, Randolph G Brewton, P M Mayne, John R Baker

    Abstract Previous studies show that the Collagen fibrils of the mammalian vitreous humor are assembled largely from type II Collagen with smaller amounts of type IX Collagen and either type V or type XI Collagen. In this paper, we report the separation of two chains of type V/type XI Collagen from type II Collagen by heparin-Sepharose chromatography. These chains were characterized by sequencing of selected cyanogen bromide or tryptic peptides with subsequent comparison of these sequences with cDNA-derived amino acid sequences of the alpha 1(V), alpha 1(XI), alpha 2(V), and alpha 2(XI) chains. The results show that vitreous fibrils are assembled from molecules containing the alpha 1(XI) and alpha 2(V) chains. These results, together with recent results from other laboratories, indicate that type V and type XI Collagens are not separate Collagen types but are part of a larger Collagen family in which chains of both type V and type XI Collagens participate in the formation of a variety of native molecules.

Raili Myllyla – One of the best experts on this subject based on the ideXlab platform.

  • secretion and assembly of type iv and vi Collagens depend on glycosylation of hydroxylysines
    Journal of Biological Chemistry, 2007
    Co-Authors: Laura Sipila, Heli Ruotsalainen, Raija Sormunen, Naomi L Baker, Shireen R Lamande, Miia Vapola, Chunguang Wang, Yoshikazu Sado, Attila Aszodi, Raili Myllyla

    Abstract Most lysines in type IV and VI Collagens are hydroxylated and glycosylated, but the functions of these unique galactosylhydroxylysyl and glucosylgalactosylhydroxylysyl residues are poorly understood. The formation of glycosylated hydroxylysines is catalyzed by multifunctional lysyl hydroxylase 3 (LH3) in vivo, and we have used LH3-manipulated mice and cells as models to study the function of these carbohydrates. These hydroxylysine-linked carbohydrates were shown recently to be indispensable for the formation of basement membranes (Ruotsalainen, H., Sipila, L., Vapola, M., Sormunen, R., Salo, A. M., Uitto, L., Mercer, D. K., Robins, S. P., Risteli, M., Aszodi, A., Fassler, R., and Myllyla, R. (2006) J. Cell Sci. 119, 625–635). Analysis of LH3 knock-out embryos and cells in this work indicated that loss of glycosylated hydroxylysines prevents the intracellular tetramerization of type VI Collagen and leads to impaired secretion of type IV and VI Collagens. Mice lacking the LH activity of LH3 produced slightly underglycosylated type IV and VI Collagens with abnormal distribution. The altered distribution and aggregation of type VI Collagen led to similar ultrastructural alterations in muscle to those detected in Collagen VI knockout and some Ullrich congenital muscmuscular dystrophy patients. Our results provide new information about the function of hydroxylysine-linked carbohydrates of Collagens, indicating that they play an important role in the secretion, assembly, and distribution of highly glycosylated Collagen types.