Our molecular map of type I collagen was previously correlated with the Orgel et al., 2006 x-ray fibril diffraction model to identify cell and matrix interaction domains. Here we used two strategies to analyze mutation patterns to pinpoint functionally significant regions. First, regions of the α1(I) chains were identified having three or more consecutive glycines either associated with lethal or silent phenotypes. Many of these regions co-localized with sites for interactions with mineralization proteins such as phosphophoryn, cell surface receptors, and matrix metalloproteinases, or for intermolecular crosslinking. Five of the larger runs of silent glycines, although each on separate monomers in the D-period, clustered vertically within a narrow fibril region- herein called the major silent zone (MSZ). Second, the distribution of OI substitution mutations on the COL1A1 and COL1A2 genes were examined and found to be statistically different from that expected on the basis of base pair mutation rates, suggesting differential phenotypic consequences of mutations occurring on different collagen regions. For example, some glycines were predicted to have high mutation rates yet did not; notably, most localized within or near the MSZ or other runs of silent glycines. Together, these results pinpointed several regions of the collagen triple helix- most notably within the cell interaction domain, and a narrow cross-fibril zone just N-terminal to the major cell surface integrin binding site GFOGER- as being particularly sensitive to glycine mutations and likely having highly crucial biological functions. Thus for some collagen mutations, disease phenotypes may result, at least in part, from disruption of crucial protein functions such as mineralization or cell-fibril interactions.

Type I collagen molecular map lends insights into the domain structure of the fibril and the genotype-phenotype relationship for some collagen mutations

MOTTES, Monica;
2013-01-01

Abstract

Our molecular map of type I collagen was previously correlated with the Orgel et al., 2006 x-ray fibril diffraction model to identify cell and matrix interaction domains. Here we used two strategies to analyze mutation patterns to pinpoint functionally significant regions. First, regions of the α1(I) chains were identified having three or more consecutive glycines either associated with lethal or silent phenotypes. Many of these regions co-localized with sites for interactions with mineralization proteins such as phosphophoryn, cell surface receptors, and matrix metalloproteinases, or for intermolecular crosslinking. Five of the larger runs of silent glycines, although each on separate monomers in the D-period, clustered vertically within a narrow fibril region- herein called the major silent zone (MSZ). Second, the distribution of OI substitution mutations on the COL1A1 and COL1A2 genes were examined and found to be statistically different from that expected on the basis of base pair mutation rates, suggesting differential phenotypic consequences of mutations occurring on different collagen regions. For example, some glycines were predicted to have high mutation rates yet did not; notably, most localized within or near the MSZ or other runs of silent glycines. Together, these results pinpointed several regions of the collagen triple helix- most notably within the cell interaction domain, and a narrow cross-fibril zone just N-terminal to the major cell surface integrin binding site GFOGER- as being particularly sensitive to glycine mutations and likely having highly crucial biological functions. Thus for some collagen mutations, disease phenotypes may result, at least in part, from disruption of crucial protein functions such as mineralization or cell-fibril interactions.
9786056402302
type I collagen
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11562/732762
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