Structural highlights
7nyd is a 8 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
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| Method: | Electron Microscopy, Resolution 3.27Å |
| Ligands: | , , , , |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Disease
CO8A_HUMAN Defects in C8A are a cause of complement component 8 deficiency type 1 (C8D1) [MIM:613790. A rare defect of the complement classical pathway associated with susceptibility to severe recurrent infections, predominantly by Neisseria gonorrhoeae or Neisseria meningitidis.
Function
CO8A_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. C8A inserts into the target membrane, but does not form pores by itself.[1] [2]
Publication Abstract from PubMed
Unregulated 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[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Steckel EW, York RG, Monahan JB, Sodetz JM. The eighth component of human complement. Purification and physicochemical characterization of its unusual subunit structure. J Biol Chem. 1980 Dec 25;255(24):11997-2005. PMID:7440581
- ↑ Hadders MA, Beringer DX, Gros P. Structure of C8alpha-MACPF reveals mechanism of membrane attack in complement immune defense. Science. 2007 Sep 14;317(5844):1552-4. PMID:17872444 doi:317/5844/1552
- ↑ Menny A, Lukassen MV, Couves EC, Franc V, Heck AJR, Bubeck D. Structural basis of soluble membrane attack complex packaging for clearance. Nat Commun. 2021 Oct 19;12(1):6086. PMID:34667172 doi:10.1038/s41467-021-26366-w
