期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2017
卷号：114
期号：13
页码：3403-3408
DOI：10.1073/pnas.1620881114
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Recognition by the leukocyte integrins αXβ2 and αMβ2 of complement iC3b-opsonized targets is essential for effector functions including phagocytosis. The integrin-binding sites on iC3b remain incompletely characterized. Here, we describe negative-stain electron microscopy and biochemical studies of αXβ2 and αMβ2 in complex with iC3b. Despite high homology, the two integrins bind iC3b at multiple distinct sites. αXβ2 uses the αX αI domain to bind iC3b on its C3c moiety at one of two sites: a major site at the interface between macroglobulin (MG) 3 and MG4 domains, and a less frequently used site near the C345C domain. In contrast, αMβ2 uses its αI domain to bind iC3b at the thioester domain and simultaneously interacts through a region near the αM β-propeller and β2 βI domain with a region of the C3c moiety near the C345C domain. Remarkably, there is no overlap between the primary binding site of αXβ2 and the binding site of αMβ2 on iC3b. Distinctive binding sites on iC3b by integrins αXβ2 and αMβ2 may be biologically beneficial for leukocytes to more efficiently capture opsonized pathogens and to avoid subversion by pathogen factors. Activation of mammalian complement is critical for the clearance of pathogens and altered host cells, whereas excessive activation results in tissue damage ( 1 ). Complement activation can be initiated by three distinct pathways with proteolytic cleavage of complement component C3 as the pivotal step in each pathway. C3 is cleaved to C3b by C3 convertases. C3b participates in some C3 convertases to amplify C3 cleavage; however, further cleavage of C3b to iC3b inactivates convertase activity. In turn, iC3b can be digested to yield C3c plus C3dg, and C3dg can be further cleaved to C3d ( 2 ) ( Fig. 1 A ). Conversion of C3 to C3b exposes the otherwise buried reactive thioester bond in the thioester domain (TED) and enables it to covalently attach to hydroxyl and amino groups on pathogenic, immunogenic, and apoptotic cell surfaces ( 3 ). Opsonic fragments of C3 covalently bound through the TED, i.e., C3b, iC3b, and C3dg/C3d serve as ligands for five distinct complement receptors (CRs). Each CR has been characterized for its preference for specific C3 opsonic fragments. CR type 3 (CR3, also known as CD11b/CD18, Mac-1, or integrin αMβ2) and CR type 4 (CR4, also known as CD11c/CD18, p150, 95, or integrin αXβ2) specifically recognize iC3b as shown by selective rosette formation with erythrocytes opsonized with iC3b but not C3b or C3d ( 4 ⇓ – 6 ), and specific isolation from cells by affinity chromatography on iC3b-Sepharose beads ( 7 ). However, at high concentrations on opsonized cells, C3d and C3dg can show reactivity with CR3 ( 8 , 9 ).
