Fibromodulin Interacts with Collagen Cross-linking Sites and Activates Lysyl Oxidase.

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Fibromodulin Interacts with Collagen Cross-linking Sites and Activates Lysyl Oxidase. / Kalamajski, Sebastian; Bihan, Dominique; Bonna, Arkadiusz; Rubin, Kristofer; Farndale, Richard W.

In: Journal of Biological Chemistry, Vol. 291, No. 15, 2016, p. 7951-79060.

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Kalamajski, Sebastian ; Bihan, Dominique ; Bonna, Arkadiusz ; Rubin, Kristofer ; Farndale, Richard W. / Fibromodulin Interacts with Collagen Cross-linking Sites and Activates Lysyl Oxidase. In: Journal of Biological Chemistry. 2016 ; Vol. 291, No. 15. pp. 7951-79060.

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TY - JOUR

T1 - Fibromodulin Interacts with Collagen Cross-linking Sites and Activates Lysyl Oxidase.

AU - Kalamajski, Sebastian

AU - Bihan, Dominique

AU - Bonna, Arkadiusz

AU - Rubin, Kristofer

AU - Farndale, Richard W

PY - 2016

Y1 - 2016

N2 - The hallmark of fibrotic disorders is a highly cross-linked and dense collagen matrix, a property driven by the oxidative action of lysyl oxidase. Other fibrosis-associated proteins also contribute to the final collagen matrix properties, one of which is fibromodulin - its interactions with collagen affect collagen cross-linking, packing, and fibril diameter. We investigated the possibility that a specific relationship exists between fibromodulin and lysyl oxidase, potentially imparting a specific collagen matrix phenotype. We mapped the fibromodulin-collagen interaction sites using the Collagen II and III Toolkit peptide libraries. Fibromodulin interacted with the peptides containing the known collagen cross-linking sites and the MMP-1 cleavage site in collagens I and II. Interestingly, the interaction sites are closely aligned within the quarter-staggered collagen fibril, suggesting a multivalent interaction between fibromodulin and several collagen helices. Furthermore, we detected an interaction between fibromodulin and lysyl oxidase - a major collagen cross-linking enzyme - and mapped the interaction site to 12 N-terminal amino acids on fibromodulin. This interaction also increases the activity of lysyl oxidase. Altogether, the data suggest a fibromodulin-modulated collagen cross-linking mechanism, where fibromodulin binds to a specific part of the collagen domain and also forms a complex together with lysyl oxidase, targeting the enzyme towards specific cross-linking sites.

AB - The hallmark of fibrotic disorders is a highly cross-linked and dense collagen matrix, a property driven by the oxidative action of lysyl oxidase. Other fibrosis-associated proteins also contribute to the final collagen matrix properties, one of which is fibromodulin - its interactions with collagen affect collagen cross-linking, packing, and fibril diameter. We investigated the possibility that a specific relationship exists between fibromodulin and lysyl oxidase, potentially imparting a specific collagen matrix phenotype. We mapped the fibromodulin-collagen interaction sites using the Collagen II and III Toolkit peptide libraries. Fibromodulin interacted with the peptides containing the known collagen cross-linking sites and the MMP-1 cleavage site in collagens I and II. Interestingly, the interaction sites are closely aligned within the quarter-staggered collagen fibril, suggesting a multivalent interaction between fibromodulin and several collagen helices. Furthermore, we detected an interaction between fibromodulin and lysyl oxidase - a major collagen cross-linking enzyme - and mapped the interaction site to 12 N-terminal amino acids on fibromodulin. This interaction also increases the activity of lysyl oxidase. Altogether, the data suggest a fibromodulin-modulated collagen cross-linking mechanism, where fibromodulin binds to a specific part of the collagen domain and also forms a complex together with lysyl oxidase, targeting the enzyme towards specific cross-linking sites.

U2 - 10.1074/jbc.M115.693408

DO - 10.1074/jbc.M115.693408

M3 - Article

C2 - 26893379

VL - 291

SP - 7951

EP - 79060

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 1083-351X

IS - 15

ER -