7nyc
cryoEM structure of 3C9-sMAC
Structural highlights
DiseaseCO7_HUMAN Immunodeficiency due to a late component of complement deficiency. Disease susceptibility is associated with variations affecting the gene represented in this entry. FunctionCO7_HUMAN Constituent of the membrane attack complex (MAC) that plays a key role in the innate and adaptive immune response by forming pores in the plasma membrane of target cells. C7 serves as a membrane anchor. Publication Abstract from PubMedUnregulated complement activation causes inflammatory and immunological pathologies with consequences for human disease. To prevent bystander damage during an immune response, extracellular chaperones (clusterin and vitronectin) capture and clear soluble precursors to the membrane attack complex (sMAC). However, how these chaperones block further polymerization of MAC and prevent the complex from binding target membranes remains unclear. Here, we address that question by combining cryo electron microscopy (cryoEM) and cross-linking mass spectrometry (XL-MS) to solve the structure of sMAC. Together our data reveal how clusterin recognizes and inhibits polymerizing complement proteins by binding a negatively charged surface of sMAC. Furthermore, we show that the pore-forming C9 protein is trapped in an intermediate conformation whereby only one of its two transmembrane beta-hairpins has unfurled. This structure provides molecular details for immune pore formation and helps explain a complement control mechanism that has potential implications for how cell clearance pathways mediate immune homeostasis. Structural basis of soluble membrane attack complex packaging for clearance.,Menny A, Lukassen MV, Couves EC, Franc V, Heck AJR, Bubeck D Nat Commun. 2021 Oct 19;12(1):6086. doi: 10.1038/s41467-021-26366-w. PMID:34667172[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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