The Experts below are selected from a list of 294 Experts worldwide ranked by ideXlab platform
Donald Gullberg - One of the best experts on this subject based on the ideXlab platform.
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α11β1 integrin recognizes the gfoger sequence in interstitial Collagens
Journal of Biological Chemistry, 2003Co-Authors: Wanming Zhang, Richard W Farndale, Carlfredrik Tiger, Jarmo Kapyla, Santeri J Puranen, Graham C Knight, Olli T Pentikainen, Mark Johnson, Jyrki Heino, Donald GullbergAbstract:Abstract The integrins α1β1, α2β1, α10β1, and α11β1 are referred to as a collagen receptor subgroup of the integrin family. Recently, both α1β1 and α2β1integrins have been shown to recognize triple-helical GFOGER (where single letter amino acid nomenclature is used, O = hydroxyproline) or GFOGER-like motifs found in Collagens, despite their distinct binding specificity for various collagen subtypes. In the present study we have investigated the mechanism whereby the latest member in the integrin family, α11β1, recognizes Collagens using C2C12 cells transfected with α11 cDNA and the bacterially expressed recombinant α11 I domain. The ligand binding properties of α11β1 were compared with those of α2β1. Mg2+-dependent α11β1 binding to type I collagen required micromolar Ca2+ but was inhibited by 1 mmCa2+, whereas α2β1-mediated binding was refractory to millimolar concentrations of Ca2+. The bacterially expressed recombinant α11 I domain preference for fibrillar Collagens over Collagens IV and VI was the same as the α2 I domain. Despite the difference in Ca2+ sensitivity, α11β1-expressing cells and the α11 I domain bound to helical GFOGER sequences in a manner similar to α2β1-expressing cells and the α2 I domain. Modeling of the α I domain-collagen peptide complexes could partially explain the observed preference of different I domains for certain GFOGER sequence variations. In summary, our data indicate that the GFOGER sequence in fibrillar Collagens is a common recognition motif used by α1β1, α2β1, and also α11β1 integrins. Although α10and α11 chains show the highest sequence identity, α2 and α11 are more similar with regard to collagen specificity. Future studies will reveal whether α2β1 and α11β1integrins also show overlapping biological functions.
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α11β1 integrin is a receptor for interstitial Collagens involved in cell migration and collagen reorganization on mesenchymal nonmuscle cells
Developmental Biology, 2001Co-Authors: Carlfredrik Tiger, Francoise Fougerousse, Gunilla Grundstrom, Teet Velling, Donald GullbergAbstract:Abstract α11β1 integrin constitutes a recent addition to the integrin family. Here, we present the first in vivo analysis of α11 protein and mRNA distribution during human embryonic development. α11 protein and mRNA were present in various mesenchymal cells around the cartilage anlage in the developing skeleton in a pattern similar to that described for the transcription factor scleraxis. α11 was also expressed by mesenchymal cells in intervertebral discs and in keratocytes in cornea, two sites with highly organized collagen networks. Neither α11 mRNA nor α11 protein could be detected in myogenic cells in human embryos. The described expression pattern is compatible with α11β1 functioning as a receptor for interstitial Collagens in vivo. To test this hypothesis in vitro, full-length human α11 cDNA was stably transfected into the mouse satellite cell line C2C12, lacking endogenous collagen receptors. α11β1 mediated cell adhesion to Collagens I and IV (with a preference for collagen I) and formed focal contacts on Collagens. In addition, α11β1 mediated contraction of fibrillar collagen gels in a manner similar to α2β1, and supported migration on collagen I in response to chemotactic stimuli. Our data support a role for α11β1 as a receptor for interstitial Collagens on mesenchymally derived cells and suggest a multifunctional role of α11β1 in the recognition and organization of interstitial collagen matrices during development.
Richard W Farndale - One of the best experts on this subject based on the ideXlab platform.
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an activating mutation reveals a second binding mode of the integrin α2 i domain to the gfoger motif in Collagens
PLOS ONE, 2013Co-Authors: Federico Carafoli, Dominique Bihan, Samir W Hamaia, Erhard Hohenester, Richard W FarndaleAbstract: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.
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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, 2011Co-Authors: Huifang Xu, Johanna Myllyharju, Nicolas Raynal, Stavros Stathopoulos, Richard W Farndale, Birgit LeitingerAbstract:The discoidin domain receptors, DDR1 and DDR2 are cell surface 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.
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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, 2010Co-Authors: Heli Elovaara, Nicolas Raynal, Richard W Farndale, Dominique Bihan, Nicholas Pugh, Sami K Kilpinen, Mikael Skurnik, Adrian GoldmanAbstract: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 collagen-binding proteins. 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 collagen-binding proteins, 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 collagen-binding proteins.
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identification of multiple potent binding sites for human leukocyte associated ig like receptor lair on Collagens ii and iii
Matrix Biology, 2009Co-Authors: Robert Jan Lebbink, Nicolas Raynal, Richard W Farndale, Dominique Bihan, Talitha De Ruiter, Linde MeyaardAbstract:Immune responses are tightly controlled by the opposing actions of activating and inhibitory immune receptors. Previously we identified Collagens as ligands for the inhibitory leukocyte-associated Ig-like receptor-1 (LAIR-1), revealing a novel mechanism of peripheral immune regulation by inhibitory immune receptors binding to extracellular matrix Collagens. This interaction can be blocked by LAIR-2, a secreted member of the LAIR-1 family. LAIR-1 specifically interacts with synthetic trimeric peptides containing 10 repeats of glycine-proline-hydroxyproline (GPO) residues which can directly inhibit immune cell activation in vitro. Here we studied the interaction of human LAIR-1 and LAIR-2 with collagen in more detail by using novel overlapping synthetic trimeric peptides (Toolkits) encompassing the entire triple-helical domain of human Collagens II and III. LAIR-1 and LAIR-2 bind several of these collagen-like peptides, with LAIR-2 being able to bind more than LAIR-1. LAIR binding to trimeric collagen peptides was influenced by GPO content of the peptide, although additional non-GPO triplets contributed to the interaction. Furthermore, we identified several trimeric peptides that were potent LAIR-1 ligands and could efficiently induce inhibition of T cell activation and FceRI-induced degranulation of RBL-2H3 cells through binding to LAIR-1. A detailed understanding of the LAIR recognition motifs within collagen may lead to the development of potent reagents that can be used in in vitro, ex vivo, and in vivo functional studies to dissect the biology and function of the collagen/LAIR-1 interaction.
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mapping of sparc bm 40 osteonectin binding sites on fibrillar Collagens
Journal of Biological Chemistry, 2008Co-Authors: Camilla Giudici, Nicolas Raynal, Richard W Farndale, Hanna Wiedemann, Wayne A Cabral, Joan C Marini, Rupert Timpl, Hans Peter Bachinger, Takako Sasaki, Ruggero TenniAbstract:Abstract The 33-kDa matrix protein SPARC (BM-40, osteonectin) binds several collagen types with moderate affinity. The collagen-binding site resides in helix αA of the extracellular calcium-binding domain of SPARC and is partially masked by helix αC. Previously, we found that the removal of helix αC caused a 10-fold increase in the affinity of SPARC for collagen, and we identified amino acids crucial for binding by site-directed mutagenesis. In this study, we used rotary shadowing, CNBr peptides, and synthetic peptides to map binding sites of SPARC onto Collagens I, II, and III. Rotary shadowing and electron microscopy of SPARC-collagen complexes identified a major binding site ∼180 nm from the C terminus of collagen. SPARC binding was also detected with lower frequency near the matrix metalloproteinase cleavage site. These data fit well with our analysis of SPARC binding to CNBr peptides, denaturation of which abolished binding, indicating triple-helical conformation of collagen to be essential. SPARC binding was substantially decreased in two of seven α2(I) mutant procollagen I samples and after N-acetylation of Lys/Hyl side chains in wild-type collagen. Synthetic peptides of collagen III were used to locate the binding sites, and we found SPARC binding activity in a synthetic triple-helical peptide containing the sequence GPOGPSGPRGQOGVMGFOGPKGNDGAO (where O indicates 4-hydroxyproline), with affinity for SPARC comparable with that of procollagen III. This sequence is conserved among α chains of Collagens I, II, III, and V. In vitro collagen fibrillogenesis was delayed in the presence of SPARC, suggesting that SPARC might modulate collagen fibril assembly in vivo.
Andrzej Fertala - One of the best experts on this subject based on the ideXlab platform.
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Designing recombinant Collagens for biomedical applications
Current Tissue Engineering, 2016Co-Authors: Andrzej Fertala, R. A. Hoffman, M. D. Shah, W.v. ArnoldAbstract:� 2016 Bentham Science Publishers. Collagens are a key element in the architecture of all organs and tissues. These proteins not only build the extracellular scaffolds that define the mechanical properties of tissues, but also play an important role as cell signaling molecules. Certain characteristics of Collagens enable them to fulfill specific functions, including their triple-helical structure and their ability to self-assemble into complex extracellular structures. Their unique properties allow Collagens to serve as a material to build scaffolds for tissue repair and engineering, as a drug delivery vehicle, and, in the form of gelatin, as a gelling agent in food, pharmaceutical, and cosmetic industries. Animal-derived Collagens are widely utilized in the biomedical field today, but their use is associated with a number of limitations and potential side effects. Efforts over the last two decades have advanced technology for the production of recombinant variants of human Collagens and collagen-like proteins. Potential applications of these proteins not only eliminate the risks associated with animal-derived Collagens, but also offer customized qualities of rationally designed collagen-like proteins. This review highlights the current state of the development of the recombinant collagen technology. Moreover, it discusses key physicochemical and biological parameters that define the collagenous nature of novel recombinant collagen variants.
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candidate cell and matrix interaction domains on the collagen fibril the predominant protein of vertebrates
Journal of Biological Chemistry, 2008Co-Authors: Shawn M. Sweeney, Joseph P. Orgel, Kevin R. Turner, Gloria A. Di Lullo, Olga Antipova, Shiamalee Perumal, Jon D. Mcauliffe, Andrzej Fertala, Steven Chen, Leena AlakokkoAbstract:Next Section Abstract Type I collagen, the predominant protein of vertebrates, polymerizes with type III and V Collagens and non-collagenous molecules into large cable-like fibrils, yet how the fibril interacts with cells and other binding partners remains poorly understood. To help reveal insights into the collagen structure-function relationship, a data base was assembled including hundreds of type I collagen ligand binding sites and mutations on a two-dimensional model of the fibril. Visual examination of the distribution of functional sites, and statistical analysis of mutation distributions on the fibril suggest it is organized into two domains. The “cell interaction domain” is proposed to regulate dynamic aspects of collagen biology, including integrin-mediated cell interactions and fibril remodeling. The “matrix interaction domain” may assume a structural role, mediating collagen cross-linking, proteoglycan interactions, and tissue mineralization. Molecular modeling was used to superimpose the positions of functional sites and mutations from the two-dimensional fibril map onto a three-dimensional x-ray diffraction structure of the collagen microfibril in situ, indicating the existence of domains in the native fibril. Sequence searches revealed that major fibril domain elements are conserved in type I Collagens through evolution and in the type II/XI collagen fibril predominant in cartilage. Moreover, the fibril domain model provides potential insights into the genotype-phenotype relationship for several classes of human connective tissue diseases, mechanisms of integrin clustering by fibrils, the polarity of fibril assembly, heterotypic fibril function, and connective tissue pathology in diabetes and aging.
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Candidate cell and matrix interaction domains on the collagen fibril, the predominant protein of vertebrates
Journal of Biological Chemistry, 2008Co-Authors: Shawn M. Sweeney, Joseph P. Orgel, Kevin R. Turner, Gloria A. Di Lullo, Olga Antipova, Shiamalee Perumal, Jon D. Mcauliffe, Andrzej Fertala, Steven Chen, Leena Ala-kokkoAbstract:Type I collagen, the predominant protein of vertebrates, polymerizes with type III and V Collagens and non-collagenous molecules into large cable-like fibrils, yet how the fibril interacts with cells and other binding partners remains poorly understood. To help reveal insights into the collagen structure-function relationship, a data base was assembled including hundreds of type I collagen ligand binding sites and mutations on a two-dimensional model of the fibril. Visual examination of the distribution of functional sites, and statistical analysis of mutation distributions on the fibril suggest it is organized into two domains. The "cell interaction domain" is proposed to regulate dynamic aspects of collagen biology, including integrin-mediated cell interactions and fibril remodeling. The "matrix interaction domain" may assume a structural role, mediating collagen cross-linking, proteoglycan interactions, and tissue mineralization. Molecular modeling was used to superimpose the positions of functional sites and mutations from the two-dimensional fibril map onto a three-dimensional x-ray diffraction structure of the collagen microfibril in situ, indicating the existence of domains in the native fibril. Sequence searches revealed that major fibril domain elements are conserved in type I Collagens through evolution and in the type II/XI collagen fibril predominant in cartilage. Moreover, the fibril domain model provides potential insights into the genotype-phenotype relationship for several classes of human connective tissue diseases, mechanisms of integrin clustering by fibrils, the polarity of fibril assembly, heterotypic fibril function, and connective tissue pathology in diabetes and aging.
Shawn M. Sweeney - One of the best experts on this subject based on the ideXlab platform.
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candidate cell and matrix interaction domains on the collagen fibril the predominant protein of vertebrates
Journal of Biological Chemistry, 2008Co-Authors: Shawn M. Sweeney, Joseph P. Orgel, Kevin R. Turner, Gloria A. Di Lullo, Olga Antipova, Shiamalee Perumal, Jon D. Mcauliffe, Andrzej Fertala, Steven Chen, Leena AlakokkoAbstract:Next Section Abstract Type I collagen, the predominant protein of vertebrates, polymerizes with type III and V Collagens and non-collagenous molecules into large cable-like fibrils, yet how the fibril interacts with cells and other binding partners remains poorly understood. To help reveal insights into the collagen structure-function relationship, a data base was assembled including hundreds of type I collagen ligand binding sites and mutations on a two-dimensional model of the fibril. Visual examination of the distribution of functional sites, and statistical analysis of mutation distributions on the fibril suggest it is organized into two domains. The “cell interaction domain” is proposed to regulate dynamic aspects of collagen biology, including integrin-mediated cell interactions and fibril remodeling. The “matrix interaction domain” may assume a structural role, mediating collagen cross-linking, proteoglycan interactions, and tissue mineralization. Molecular modeling was used to superimpose the positions of functional sites and mutations from the two-dimensional fibril map onto a three-dimensional x-ray diffraction structure of the collagen microfibril in situ, indicating the existence of domains in the native fibril. Sequence searches revealed that major fibril domain elements are conserved in type I Collagens through evolution and in the type II/XI collagen fibril predominant in cartilage. Moreover, the fibril domain model provides potential insights into the genotype-phenotype relationship for several classes of human connective tissue diseases, mechanisms of integrin clustering by fibrils, the polarity of fibril assembly, heterotypic fibril function, and connective tissue pathology in diabetes and aging.
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Candidate cell and matrix interaction domains on the collagen fibril, the predominant protein of vertebrates
Journal of Biological Chemistry, 2008Co-Authors: Shawn M. Sweeney, Joseph P. Orgel, Kevin R. Turner, Gloria A. Di Lullo, Olga Antipova, Shiamalee Perumal, Jon D. Mcauliffe, Andrzej Fertala, Steven Chen, Leena Ala-kokkoAbstract:Type I collagen, the predominant protein of vertebrates, polymerizes with type III and V Collagens and non-collagenous molecules into large cable-like fibrils, yet how the fibril interacts with cells and other binding partners remains poorly understood. To help reveal insights into the collagen structure-function relationship, a data base was assembled including hundreds of type I collagen ligand binding sites and mutations on a two-dimensional model of the fibril. Visual examination of the distribution of functional sites, and statistical analysis of mutation distributions on the fibril suggest it is organized into two domains. The "cell interaction domain" is proposed to regulate dynamic aspects of collagen biology, including integrin-mediated cell interactions and fibril remodeling. The "matrix interaction domain" may assume a structural role, mediating collagen cross-linking, proteoglycan interactions, and tissue mineralization. Molecular modeling was used to superimpose the positions of functional sites and mutations from the two-dimensional fibril map onto a three-dimensional x-ray diffraction structure of the collagen microfibril in situ, indicating the existence of domains in the native fibril. Sequence searches revealed that major fibril domain elements are conserved in type I Collagens through evolution and in the type II/XI collagen fibril predominant in cartilage. Moreover, the fibril domain model provides potential insights into the genotype-phenotype relationship for several classes of human connective tissue diseases, mechanisms of integrin clustering by fibrils, the polarity of fibril assembly, heterotypic fibril function, and connective tissue pathology in diabetes and aging.
Carlfredrik Tiger - One of the best experts on this subject based on the ideXlab platform.
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α11β1 integrin recognizes the gfoger sequence in interstitial Collagens
Journal of Biological Chemistry, 2003Co-Authors: Wanming Zhang, Richard W Farndale, Carlfredrik Tiger, Jarmo Kapyla, Santeri J Puranen, Graham C Knight, Olli T Pentikainen, Mark Johnson, Jyrki Heino, Donald GullbergAbstract:Abstract The integrins α1β1, α2β1, α10β1, and α11β1 are referred to as a collagen receptor subgroup of the integrin family. Recently, both α1β1 and α2β1integrins have been shown to recognize triple-helical GFOGER (where single letter amino acid nomenclature is used, O = hydroxyproline) or GFOGER-like motifs found in Collagens, despite their distinct binding specificity for various collagen subtypes. In the present study we have investigated the mechanism whereby the latest member in the integrin family, α11β1, recognizes Collagens using C2C12 cells transfected with α11 cDNA and the bacterially expressed recombinant α11 I domain. The ligand binding properties of α11β1 were compared with those of α2β1. Mg2+-dependent α11β1 binding to type I collagen required micromolar Ca2+ but was inhibited by 1 mmCa2+, whereas α2β1-mediated binding was refractory to millimolar concentrations of Ca2+. The bacterially expressed recombinant α11 I domain preference for fibrillar Collagens over Collagens IV and VI was the same as the α2 I domain. Despite the difference in Ca2+ sensitivity, α11β1-expressing cells and the α11 I domain bound to helical GFOGER sequences in a manner similar to α2β1-expressing cells and the α2 I domain. Modeling of the α I domain-collagen peptide complexes could partially explain the observed preference of different I domains for certain GFOGER sequence variations. In summary, our data indicate that the GFOGER sequence in fibrillar Collagens is a common recognition motif used by α1β1, α2β1, and also α11β1 integrins. Although α10and α11 chains show the highest sequence identity, α2 and α11 are more similar with regard to collagen specificity. Future studies will reveal whether α2β1 and α11β1integrins also show overlapping biological functions.
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α11β1 integrin is a receptor for interstitial Collagens involved in cell migration and collagen reorganization on mesenchymal nonmuscle cells
Developmental Biology, 2001Co-Authors: Carlfredrik Tiger, Francoise Fougerousse, Gunilla Grundstrom, Teet Velling, Donald GullbergAbstract:Abstract α11β1 integrin constitutes a recent addition to the integrin family. Here, we present the first in vivo analysis of α11 protein and mRNA distribution during human embryonic development. α11 protein and mRNA were present in various mesenchymal cells around the cartilage anlage in the developing skeleton in a pattern similar to that described for the transcription factor scleraxis. α11 was also expressed by mesenchymal cells in intervertebral discs and in keratocytes in cornea, two sites with highly organized collagen networks. Neither α11 mRNA nor α11 protein could be detected in myogenic cells in human embryos. The described expression pattern is compatible with α11β1 functioning as a receptor for interstitial Collagens in vivo. To test this hypothesis in vitro, full-length human α11 cDNA was stably transfected into the mouse satellite cell line C2C12, lacking endogenous collagen receptors. α11β1 mediated cell adhesion to Collagens I and IV (with a preference for collagen I) and formed focal contacts on Collagens. In addition, α11β1 mediated contraction of fibrillar collagen gels in a manner similar to α2β1, and supported migration on collagen I in response to chemotactic stimuli. Our data support a role for α11β1 as a receptor for interstitial Collagens on mesenchymally derived cells and suggest a multifunctional role of α11β1 in the recognition and organization of interstitial collagen matrices during development.