Candidate Cell and Matrix Interaction Domains on the Collagen Fibril, the Predominant Protein of Vertebrates

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. 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. Type I collagen is the most abundant protein in humans and other vertebrates, comprising much of the fibrous extracellular matrix scaffold of bones, tendons, skin, and many other tissues (1Piez K.A. Reddi A.H. Extracellular Matrix Biochemistry. Elsevier, New York1984Google Scholar, 2Ayad S. Boot-handford R.P. Humpries M.J. Kadler K.E. Shuttleworth C.A. The Extracellular Matrix Facts Book. 2nd Ed. Academic Press, San Diego1998Google Scholar, 3Prockop D.J. Kivirikko K.I. Annu. Rev. Biochem. 1995; 64: 403-434Crossref PubMed Scopus (1368) Google Scholar, 4Kadler K.E. Baldock C. Bella J. Boot-Handford R.P. J. Cell Sci. 2007; 120: 1955-1958Crossref PubMed Scopus (536) Google Scholar). In general, type I collagen and its binding partners are proposed to provide mechanical strength and form to tissues. Collagenous scaffolds are laid down and remodeled by cells and are also a predominant substrate for cell interactions, migration, and differentiation. Consequently, various debilitating human diseases are associated with type I collagen mutations, including osteogenesis imperfecta (OI, 2The abbreviations used are: OI, osteogenesis imperfecta; PG, proteoglycan; THP, triple helical peptide; MLBR, major ligand binding region; MMP, matrix metalloproteinase; SPARC, secreted protein, acidic, and rich in cysteine; FACIT, fibril-associated collagens with interrupted triple helices. 2The abbreviations used are: OI, osteogenesis imperfecta; PG, proteoglycan; THP, triple helical peptide; MLBR, major ligand binding region; MMP, matrix metalloproteinase; SPARC, secreted protein, acidic, and rich in cysteine; FACIT, fibril-associated collagens with interrupted triple helices. brittle bone disease), Ehlers Danlos syndrome, vascular disorders, and others (3Prockop D.J. Kivirikko K.I. Annu. Rev. Biochem. 1995; 64: 403-434Crossref PubMed Scopus (1368) Google Scholar, 5Marini J.C. Forlino A. Cabral W.A. Barnes A.M. San Antonio J.D. Milgrom S. Hyland J.C. Korkko J. Prockop D.J. Paepe A.De Coucke P. Symoens S. Glorieux F.H. Roughley P.J. Lund A.M. Kuurila-Svahn K. Hartikka H. Cohn D.H. Krakow D. Mottes M. Schwarze U. Chen D. Yang K. Kuslich C. Troendle J. Dalgleish R. Byers P.H. Hum. Mutat. 2007; 28: 209-221Crossref PubMed Scopus (538) Google Scholar). Type I collagen is also employed in human medicine as hemostatic sponges and implants to repair wounds and in tissue engineering applications as scaffolds (6Yang C. Hillas P.J. Baez J.A. Nokelainen M. Balan J. Tang J. Spiro R. Polarek J.W. BioDrugs. 2004; 18: 103-119Crossref PubMed Scopus (263) Google Scholar). Type I collagen is synthesized in the endoplasmic reticulum as α1 and α2 procollagen chains, each encoded by separate genes that are translated into proteins somewhat longer than 1000 amino acid residues (3Prockop D.J. Kivirikko K.I. Annu. Rev. Biochem. 1995; 64: 403-434Crossref PubMed Scopus (1368) Google Scholar, 7Prockop D.J. Kivirikko K.I. N. Engl. J. Med. 1984; 311: 376-386Crossref PubMed Scopus (396) Google Scholar). Nucleation domains on the C-terminal propeptide promote the polymerization of two α1 and one α2 chains into the procollagen triple helical monomer (Fig. 1, A and B). The triple helical domain of procollagen is composed of contiguous glycine-X-Y tri-peptide repeats, with the obligate glycine in the first position as its side chain is the only one small enough to fit within the coiled-coil of the triple helix. Extracellularly, N- and C-proteinases remove the globular termini of procollagen, and every ∼67 nm along the fiber axis, five monomers assemble in a quarter-staggered fashion to form part of the supramolecular “helix,” the microfibril. Each microfibril, the proposed subunit of the collagen fibril (Fig. 1, C-E), and its immediate microfibrillar neighbors are connected by N- and C-terminal intermolecular cross-links. The basic repeating morphological structure of the fibril is the D-period, ∼67 nm long, and composed of one overlap and one gap zone. Each D-period contains the complete monomer sequence derived from overlapping consecutive elements of five monomers (Fig. 1C, box). Other collagens, proteoglycans (PGs), and matrix macromolecules may further assemble with the fibril to impart tissue-specific properties to the heterotypic polymer (2Ayad S. Boot-handford R.P. Humpries M.J. Kadler K.E. Shuttleworth C.A. The Extracellular Matrix Facts Book. 2nd Ed. Academic Press, San Diego1998Google Scholar, 4Kadler K.E. Baldock C. Bella J. Boot-Handford R.P. J. Cell Sci. 2007; 120: 1955-1958Crossref PubMed Scopus (536) Google Scholar, 8Scott J.E. Biochem. J. 1988; 252: 313-323Crossref PubMed Scopus (543) Google Scholar). However, it is unclear how cells, matrix molecules, and other factors interact with the heterotypic collagen fibril. Therefore, a comprehensive structure-function model of the protein has been To help type I collagen structure-function a data base of functional ligand binding sites, and human mutations to type I collagen was assembled and as a two-dimensional map of the collagen fibril Korkko J. San Antonio J.D. J. PubMed Scopus Google Scholar). was that on collagen, and the positions of classes of mutations may with the and of type I collagen been through x-ray diffraction A. Sci. U. S. A. PubMed Scopus Google Scholar). is a analysis of the hundreds of functional sites, and mutations on the collagen Moreover, the map is of a three-dimensional model of the collagen microfibrillar structure that was S. Sci. U. S. A. PubMed Scopus Google Scholar). analysis insights into how the type I collagen and collagen in general, are organized to as scaffolds for cell interactions and as the predominant structural elements of tissues. and of binding sites and functional domains from the and are by to the for sites on of the map in the sites are in to of interactions and of collagen fibrils, as by are by binding on as of the other the of collagen model triple helical K.A. K. H. J. PubMed Scopus Google Scholar, J. San Antonio J.D. J. PubMed Scopus Google in including composed of of collagen D. S. N. A. N. Biochem. PubMed Scopus Google has of the positions of various ligand binding sites and functional domains on the collagen binding and mutation map of the human type I collagen fibril. of the triple are and and are as the the position in glycine-X-Y that from a in in the protein data in the the of to mutations with H. H. H. K. 2004; PubMed Scopus Google its binding are by to ligand binding to type I procollagen to chains binding 1, and are by the integrin binding N- and C-terminal intermolecular for many of the functional domains on collagen are in the first map Korkko J. San Antonio J.D. J. PubMed Scopus Google and in the New sites on the map M. D. A. P. J. PubMed Scopus Google S. K. J. PubMed Scopus Google and domains W.A. A. S. J.C. J. PubMed Scopus Google Scholar, Cabral W.A. J.C. S. J. PubMed Scopus Google domain S. Sci. U. S. A. PubMed Scopus Google substrate R. Chen J. M. P. Glorieux F.H. J. Schwarze U. Byers P.H. M. PubMed Scopus Google H. A. S. PubMed Scopus Google R. H. PubMed Scopus Google Scholar, A. Chen M. PubMed Scopus Google N. D. PubMed Scopus Google domain N. D. J. PubMed Scopus Google and of on J. San Antonio J.D. J. PubMed Scopus Google cell D. J. 2004; PubMed Scopus Google and J. A. 2004; PubMed Scopus Google Scholar). from the was from a Korkko J. San Antonio J.D. J. PubMed Scopus Google In type I interactions may the tissue Moreover, collagen may other collagens as III and V Cell of Extracellular Press, New Google in the fibril are and that However, the of in the and that in the data base Korkko J. San Antonio J.D. J. PubMed Scopus Google the is to of collagen structure and on of and by on the functional elements of binding sites and functional domains in as on the collagen monomer to than one ligand has been to that are as that within the of a fibril to a and as binding sites on monomers within the In it is proposed that interactions on monomers may binding sites within the D-period, and two-dimensional structure to than one triple and ligand on sites on two monomers are as overlap with to to the of the and monomers and data from the two-dimensional map with the three-dimensional structure of collagen within the A. Sci. U. S. A. PubMed Scopus Google Scholar, A. PubMed Scopus Google Scholar). with a collagen microfibril model used in was composed from the structure of type I collagen molecules in as A. Sci. U. S. A. PubMed Scopus Google Scholar). diffraction data from native and was used to the in structure of the collagen molecules and microfibril A. PubMed Scopus Google Scholar). A model was on the of the α1 and α2 chains of type I collagen, and the from structure The map the microfibril has a of nm in the of the fiber and nm in the to To the position of functional sites from the two-dimensional collagen map on the three-dimensional microfibril and was J.A. R. PubMed Scopus Google with the of sites by of to each and the microfibril assembled by the and by structure A. Sci. U. S. A. PubMed Scopus Google Scholar). To from the of of triple a The was in the to the positions of functional and binding and human collagen protein are the of functional domains of human type I collagen on the type I collagen microfibril. of modeling of integrin binding to the collagen triple was on a the A model of the collagen I triple was A. J. 1995; PubMed Scopus Google with a acid the to and a to of human collagen in a was to To the amino was with and the with The model was a and to repeating of and C. S. P. J. 1984; Scopus Google Scholar). To the interaction of the sequence with the integrin a structure of a the and a triple helical collagen was used The intermolecular of the interaction was with the to binding of the molecules from the of Type I and Type III the mutation data base J.C. Forlino A. Cabral W.A. Barnes A.M. San Antonio J.D. Milgrom S. Hyland J.C. Korkko J. Prockop D.J. Paepe A.De Coucke P. Symoens S. Glorieux F.H. Roughley P.J. Lund A.M. Kuurila-Svahn K. Hartikka H. Cohn D.H. Krakow D. Mottes M. 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H. H. H. H. H. H. C. M. R. and D. of mutation distributions on the collagen fibril and in the The collagen map (Fig. of the protein of the human α1 and α2 chains of type I collagen, as are proposed to in the positions of structural ligand binding sites, and mutations are the distribution of sites was on the on the C-terminal of the collagen monomer (Fig. as Korkko J. San Antonio J.D. J. PubMed Scopus Google Scholar). Moreover, of ligand binding are as major ligand binding The potential functional of of the overlapping ligand binding sites Korkko J. San Antonio J.D. J. PubMed Scopus Google Scholar). A and for the first on the map on and sequence (Fig. as the predominant integrin and cell binding sequence of type I collagen D.J. Barnes M.J. J. PubMed Scopus Google Scholar, Barnes M.J. J. PubMed Scopus Google Scholar, J. J. D. J. PubMed Scopus Google Scholar). are cell that extracellular matrix molecules and are proposed to in tissue matrix assembly, and cell PubMed Scopus Google Scholar, Cell of Extracellular Press, New and Google Scholar). and modeling that of the triple with of ligand binding sites and with the of in the of the triple J.A. J. PubMed Scopus Google Scholar). the other analysis of in the triple on collagens with mutations two large triple helical that with proposed for and ligand overlap with and A.M. Cabral W.A. Barnes A.M. D.J. J.C. S. J. PubMed Scopus Google Scholar). binding sites for many of the major on monomers the two-dimensional fibril map (Fig. for the native collagen fibril it is yet of sites are for cell and ligand of the most of mutations on the associated with OI, are in proposed to from of collagen monomer is into type I III and J.C. Forlino A. Cabral W.A. Barnes A.M. San Antonio J.D. Milgrom S. Hyland J.C. Korkko J. Prockop D.J. Paepe A.De Coucke P. Symoens S. Glorieux F.H. Roughley P.J. Lund A.M. Kuurila-Svahn K. Hartikka H. Cohn D.H. Krakow D. Mottes M. Schwarze U. Chen D. Yang K. Kuslich C. Troendle J. Dalgleish R. Byers P.H. Hum. Mutat. 2007; 28: 209-221Crossref PubMed Scopus (538) Google Scholar). The model the in the to mutations the collagen and in a P.H. J. Med. 28: PubMed Scopus Google Scholar). However, several to J.C. Forlino A. Cabral W.A. Barnes A.M. San Antonio J.D. Milgrom S. Hyland J.C. Korkko J. Prockop D.J. Paepe A.De Coucke P. Symoens S. Glorieux F.H. Roughley P.J. Lund A.M. Kuurila-Svahn K. Hartikka H. Cohn D.H. Krakow D. Mottes M. Schwarze U. Chen D. Yang K. Kuslich C. Troendle J. Dalgleish R. Byers P.H. Hum. Mutat. 2007; 28: 209-221Crossref PubMed Scopus (538) Google most to the was the that of mutations with cell and on the chain of mutations to with of interactions (Fig. J.C. Forlino A. Cabral W.A. Barnes A.M. San Antonio J.D. Milgrom S. Hyland J.C. Korkko J. Prockop D.J. Paepe A.De Coucke P. Symoens S. Glorieux F.H. Roughley P.J. Lund A.M. Kuurila-Svahn K. Hartikka H. Cohn D.H. Krakow D. Mottes M. Schwarze U. Chen D. Yang K. Kuslich C. Troendle J. Dalgleish R. Byers P.H. Hum. Mutat. 2007; 28: 209-221Crossref PubMed Scopus (538) Google Scholar). New from the collagen map the for intermolecular is associated with several mutations is by mutations, and sites for and with mutation that may (Fig. mutations also to N- to C-terminal of yet to several of the fibril D-period of the examination of the collagen map a that much of the fibril is by (2Ayad S. Boot-handford R.P. Humpries M.J. Kadler K.E. Shuttleworth C.A. The Extracellular Matrix Facts Book. 2nd Ed. Academic Press, San Diego1998Google Scholar, 8Scott J.E. Biochem. 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J. 2004; PubMed Scopus Google Scholar). is proposed that the and properties of heterotypic may to of collagens of one type V collagen, integrin binding the position and in the type I may cell interactions and fibril in tissues of collagen are as the and the of type I and type collagens and partners may the domain structure assemble in into the heterotypic functional domains into mutations in type I and III collagens of triple helical yet to of the fibril However, collagen monomer into in most in a is also and a in tissue and repair K.E. J.A. J.A. Biochem. J. PubMed Scopus Google Scholar). is that proposed to the most sequence of type I collagen, is the N- and C-terminal cross-links. Therefore, monomers assemble in a into fibrils, remains for cell of domain structure of the collagen microfibril was in the of the collagen fibril (Fig. the structure of the collagen fibril remains assume in sites may as has been for J.E. Biochem. 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