Complement Receptor 3 Forms a Compact High-Affinity Complex with iC3b

被引:19
|
作者
Jensen, Rasmus K. [1 ]
Bajic, Goran [2 ,3 ,4 ]
Sen, Mehmet [5 ]
Springer, Timothy A. [6 ,7 ]
Vorup-Jensen, Thomas [8 ]
Andersen, Gregers R. [1 ]
机构
[1] Aarhus Univ, Dept Mol Biol & Genet, Gustav Wieds Vej 10C, DK-8000 Aarhus, Denmark
[2] Harvard Med Sch, Lab Mol Med, Boston Childrens Hosp, Boston, MA USA
[3] Harvard Med Sch, Dept Pediat, Boston, MA USA
[4] Icahn Sch Med Mt Sinai, Dept Microbiol, New York, NY USA
[5] Univ Houston, Dept Biol & Biochem, Houston, TX USA
[6] Harvard Med Sch, Dept Biol Chem & Mol Pharmacol, Boston, MA USA
[7] Boston Childrens Hosp, Program Cellular & Mol Med, Boston, MA USA
[8] Aarhus Univ, Dept Biomed, Aarhus, Denmark
来源
JOURNAL OF IMMUNOLOGY | 2021年 / 206卷 / 12期
关键词
INTEGRIN MAC-1 CD11B/CD18; I-DOMAIN; STRUCTURAL BASIS; MOLECULAR-BASIS; COMPONENT C3; RECOGNITION; BINDING; ACTIVATION; ADHESION; ANTIBODY;
D O I
10.4049/jimmunol.2001208
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
Complement receptor 3 (CR3, also known as Mac-1, integrin aMb2, or CD11b/CD18) is expressed on a subset of myeloid and certain activated lymphoid cells. CR3 is essential for the phagocytosis of complement-opsonized particles such as pathogens and apoptotic or necrotic cells opsonized with the complement fragment iC3b and, to a lesser extent, C3dg. Although the interaction between the iC3b thioester domain and the ligand binding CR3 (alpha M) I-domain is structurally and functionally well characterized, the nature of additional CR3-iC3b interactions required for phagocytosis of complement-opsonized objects remains obscure. In this study, we analyzed the interaction between iC3b and the 150-kDa headpiece fragment of the CR3 ectodomain. Surface plasmon resonance experiments demonstrated a 30 nM affinity of the CR3 headpiece for iC3b compared with 515 nM for the iC3b thioester domain, whereas experiments monitoring binding of iC3b to CR3-expressing cells suggested an affinity of 50 nM for the CR3-iC3b interaction. Small angle x-ray scattering analysis revealed that iC3b adopts an extended but preferred conformation in solution. Upon interaction with CR3, iC3b rearranges to form a compact receptor-ligand complex. Overall, the data suggest that the iC3b-CR3 interaction is of high affinity and relies on minor contacts formed between CR3 and regions outside the iC3b thioester domain. Our results rationalize the more efficient phagocytosis elicited by iC3b than by C3dg and pave the way for the development of specific therapeutics for the treatment of inflammatory and neurodegenerative diseases that do not interfere with the recognition of noncomplement CR3 ligands.
引用
收藏
页码:3032 / 3042
页数:11
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