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J Biol Chem. 2017 Oct 13;292(41):16970-16982. doi: 10.1074/jbc.M117.798603. Epub 2017 Sep 1.

Proteolytic processing of lysyl oxidase-like-2 in the extracellular matrix is required for crosslinking of basement membrane collagen IV.

Author information

1
From the Department of Medicine, Division of Nephrology and Hypertension and.
2
Center for Matrix Biology, Vanderbilt University Medical Center, Nashville, Tennessee 37232.
3
From the Department of Medicine, Division of Nephrology and Hypertension and roberto.vanacore@vanderbilt.edu.

Abstract

Lysyl oxidase-like-2 (LOXL2) is an enzyme secreted into the extracellular matrix that crosslinks collagens by mediating oxidative deamination of lysine residues. Our previous work demonstrated that this enzyme crosslinks the 7S domain, a structural domain that stabilizes collagen IV scaffolds in the basement membrane. Despite its relevant role in extracellular matrix biosynthesis, little is known about the structural requirements of LOXL2 that enable collagen IV crosslinking. In this study, we demonstrate that LOXL2 is processed extracellularly by serine proteases, generating a 65-kDa form lacking the first two scavenger receptor cysteine-rich domains. Site-specific mutagenesis to prevent proteolytic processing generated a full-length enzyme that is active in vitro toward a soluble substrate, but fails to crosslink insoluble collagen IV within the extracellular matrix. In contrast, the processed form of LOXL2 binds to collagen IV and crosslinks the 7S domain. Together, our data demonstrate that proteolytic processing is an important event that allows LOXL2-mediated crosslinking of basement membrane collagen IV.

KEYWORDS:

LOXL2; basement membrane; collagen; enzyme processing; extracellular matrix; lysyl oxidase; posttranslational modification (PTM); protein crosslinking; proteolytic processing

PMID:
28864775
PMCID:
PMC5641870
DOI:
10.1074/jbc.M117.798603
[Indexed for MEDLINE]
Free PMC Article

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