The chaperone also directly associates with amyloid-beta fibrils formed from the polymerizing Aβ peptide and prevents peptide aggregation 20, 21. Within sMAC, clusterin binds fluid-phase oligomeric complement complexes generated during an immune response 12 and inhibits polymerization of C9 19. Upregulated in response to cellular stress 18, clusterin recognizes a variety of cellular targets and trafficks cargo for disposal. While these studies have contributed to our understanding of the final pore, little is known of how regulators trap transition states and clear activation byproducts.Ĭlusterin (also called apolipoprotein J) is a chaperone that broadly protects against pathogenic aggregation of proteins.
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Structures of MAC 15, 16 and soluble C9 17 show that complement proteins undergo substantial conformational rearrangements to enable pore formation. In both sMAC and MAC, complement proteins associate through their pore-forming membrane attack complex perforin (MACPF) domain 14, 15. Derived from MAC precursors, sMAC is a model system for understanding structural transitions underpinning MAC assembly. sMAC, also known as sC5b9, is composed of the complement proteins C5b, C6, C7, C8 and C9 together with the extracellular regulatory proteins, clusterin and vitronectin 12, 13. While in healthy individuals sMAC exists in trace amounts, these levels are dramatically elevated during an immune response, providing a biomarker for infectious and autoimmune disease 7, 8, transplant 9, 10 and trauma 11. Soluble MAC (sMAC) is an immune activation complex that is formed from MAC assembly precursors released into plasma and scavenged by blood-based chaperones. Therefore, understanding how MAC is controlled is essential for our ability to tune the activity of a potent innate immune effector and prevent human disease. When released from complement-opsonized pathogens, these complexes can also deposit on nearby macrophages and initiate a cascade of inflammatory responses causing bystander damage 6. However, complexes that have improperly assembled on bacterial target membranes are shed into plasma and are capable of lysing red blood cells 5. An inhibitory protein blocks MAC assembly and pore formation that occurs directly on the plasma membrane of human cells 4. Therefore, MAC is highly regulated on human cells to prevent damage 2, 3. One of the first lines of defence against Gram-negative bacteria 1, MAC is a potent weapon of the innate immune system that can rupture lipid bilayers of any composition. The complement membrane attack complex (MAC) is an immune pore that directly kills pathogens and causes human disease if left unchecked.
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. Furthermore, we show that the pore-forming C9 protein is trapped in an intermediate conformation whereby only one of its two transmembrane β-hairpins has unfurled. Together our data reveal how clusterin recognizes and inhibits polymerizing complement proteins by binding a negatively charged surface of sMAC. Here, we address that question by combining cryo electron microscopy (cryoEM) and cross-linking mass spectrometry (XL-MS) to solve the structure of sMAC. However, how these chaperones block further polymerization of MAC and prevent the complex from binding target membranes remains unclear. To prevent bystander damage during an immune response, extracellular chaperones (clusterin and vitronectin) capture and clear soluble precursors to the membrane attack complex (sMAC). Unregulated complement activation causes inflammatory and immunological pathologies with consequences for human disease.
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