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Originally published In Press as doi:10.1074/jbc.M201461200 on March 12, 2002

J. Biol. Chem., Vol. 277, Issue 20, 17511-17519, May 17, 2002
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Mannose-binding Lectin (MBL) Mutants Are Susceptible to Matrix Metalloproteinase Proteolysis
POTENTIAL ROLE IN HUMAN MBL DEFICIENCY*

Georgina S. ButlerDagger §, Derek Sim||, Eric Tam||, Dana Devine||**, and Christopher M. OverallDagger ||Dagger Dagger

From the Departments of Dagger  Oral Biological and Medical Sciences, || Biochemistry and Molecular Biology, and ** Pathology, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada

Mannose-binding lectin (MBL) plays a critical role in innate immunity. Point mutations in the collagen-like domain (R32C, G34D, or G37E) of MBL cause a serum deficiency, predisposing patients to infections and diseases such as rheumatoid arthritis. We examined whether MBL mutants show enhanced susceptibility to proteolysis by matrix metalloproteinases (MMPs), which are important mediators in inflammatory tissue destruction. Human and rat MBL were resistant to proteolysis in the native state but were cleaved selectively within the collagen-like domain by multiple MMPs after heat denaturation. In contrast, rat MBL with mutations homologous to those of the human variants (R23C, G25D, or G28E) was cleaved efficiently without denaturation in the collagen-like domain by MMP-2 and MMP-9 (gelatinases A and B) and MMP-14 (membrane type-1 MMP), as well as by MMP-1 (collagenase-1), MMP-8 (neutrophil collagenase), MMP-3 (stromelysin-1), neutrophil elastase, and bacterial collagenase. Sites and order of cleavage of the rat MBL mutants for MMP-2 and MMP-9 were: Gly45-Lys46 right-arrow Gly51-Ser52 right-arrow Gly63-Gln64 right-arrow Asn80-Met81 which differed from that of MMP-14, Gly39-Leu40 right-arrow Asn80-Met81, revealing that the MMPs were not functionally interchangeable. These sites were homologous to those cleaved in denatured human MBL. Hence, perturbation of the collagen-like structure of MBL by natural mutations or by denaturation renders MBL susceptible to MMP cleavage. MMPs are likely to contribute to MBL deficiency in individuals with variant alleles and may also be involved in clearance of MBL and modulation of the host response in normal individuals.

* This work was supported in part by grants from the Canadian Institute of Health Research (to C. M. O. and D. D.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

§ Recipient of a Wellcome Trust United Kingdom traveling fellowship.

To whom correspondence should be addressed: J. B. Macdonald Bldg., 2199 Wesbrook Mall, University of British Columbia, Vancouver V6T 1Z3, Canada. Tel.: 1-604-822-2958 or 1-604-822-3561; Fax: 1-604-822-3562; E-mail: gsbutler@interchange.ubc.ca or chris.overall{at}ubc.ca.

Dagger Dagger Holder of Canada Research Chair in Metalloproteinase Biology.

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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