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J. Biol. Chem., Vol. 276, Issue 46, 43087-43094, November 16, 2001
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From the Department of Molecular Biology and Biochemistry,
University of California, Irvine, California 92697
Mannan-binding lectin (MBL) constitutes an
important part of the human innate immune defense system. It has been
shown to mediate the activation of complement upon binding to specific microbial carbohydrate motifs, to directly opsonize organisms, and to
enhance the phagocytosis of targets suboptimally opsonized with IgG or
complement components C3b or C4b. This enhancement of phagocytic
activity induced by MBL and other molecules that contain a
collagen-like region contiguous with a pattern recognition domain is
mediated by a 126,000 Mr surface glycoprotein, designated C1qRP. Although it has been known that the
collagen-like domain of these "defense collagens" contains the
interaction site(s) that triggers this enhancement of uptake, the
specific interaction site has not been identified. To address this
issue, wild type and mutant MBL constructs were generated, inserted
into baculovirus, expressed in Sf9 cells, and the recombinant
MBL (rMBL) proteins purified by mannan affinity chromatography. The
effect of wild type and mutant rMBL on the phagocytosis of targets
suboptimally opsonized with IgG or with IgM and C4b by human peripheral
blood monocytes was then assessed. Two mutants, one of which has five GXY triplets deleted below the kink region of MBL and the
other one having only two of the GXY triplets deleted below
the kink, failed to enhance phagocytosis, suggesting the importance of
the specific sequence GEKGEP in stimulating phagocytic activity.
Similar sequences were detected in other defense collagens, implicating the consensus motif GE(K/Q/R)GEP as critical in mediating the enhancement of phagocytosis through C1qRP. Clarification of
specific ligand-C1qRP interactions should facilitate the
investigation of the signal transduction processes involved in the cell
activation, as well as provide the basis for the design of specific
modulators of the functions mediated by this receptor.
Identification of a Site on Mannan-binding Lectin Critical for
Enhancement of Phagocytosis*
*
These studies were supported by Grant AI41090 from National
Institutes of Health (to A. J. T.). Support for obtaining human blood
products used in this study was provided in part by Public Health
Service Research Grant M01 RR00827 from the National Center for
Research Resources.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.
To whom correspondence should be addressed: 3205 Biological
Sciences II, Dept. of Molecular Biology and Biochemistry, University of
California, Irvine, CA 92697. Tel.: 949-824-3268; Fax: 949-824-8551; E-mail: atenner@uci.edu.
Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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