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J Biol Chem. 2016 Apr 8;291(15):7951-60. doi: 10.1074/jbc.M115.693408. Epub 2016 Feb 18.

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

Author information

1
From the Department of Laboratory Medical Sciences, Lund University, Medicon Village 406-3, 22363 Lund, Sweden and sebastian.kalamajski@med.lu.se.
2
the Department of Biochemistry, Downing Site, University of Cambridge, Cambridge CB2 1QW, United Kingdom.
3
From the Department of Laboratory Medical Sciences, Lund University, Medicon Village 406-3, 22363 Lund, Sweden and.
4
the Department of Biochemistry, Downing Site, University of Cambridge, Cambridge CB2 1QW, United Kingdom rwf10@cam.ac.uk.

Abstract

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. Together, 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 with lysyl oxidase, targeting the enzyme toward specific cross-linking sites.

KEYWORDS:

collagen; cross-linking; extracellular matrix; fibromodulin; lysyl oxidase; small leucine-rich proteoglycan (SLRP)

PMID:
26893379
PMCID:
PMC4825002
DOI:
10.1074/jbc.M115.693408
[Indexed for MEDLINE]
Free PMC Article

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