3t5o

Publication Abstract from PubMed

The complement Membrane Attack Complex (MAC) is formed by the sequential assembly of C5b with 4 homologous proteins: one copy each of C6, C7 and C8, and 12-14 copies of C9. Together these form a lytic pore in bacterial membranes. C6 through C9 comprise a MACPF domain flanked by 4-9 auxiliary domains. Here, we report the crystal structure of C6, the first and longest of the pore proteins to be recruited by C5b. Comparisons with the structures of the C8alphabetagamma heterodimer and perforin show that the central domain of C6 adopts a closed (perforin-like) state that is distinct from the open conformations in C8. We further show that C6, C8alpha and C8beta contain 3 homologous subdomains (upper, lower and regulatory) related by rotations about 2 hinge-points. In C6, the regulatory segment comprises 4 auxiliary domains that stabilize the closed conformation, inhibiting release of membrane-inserting elements. In C8beta, rotation of the regulatory segment is linked to an opening of the central beta-sheet of its clockwise partner, C8alpha. These observations lead us to propose a model for initiation and unidirectional propagation of MAC assembly in which the auxiliary domains play key roles: in the assembly of the C5b-8 initiation complex; in driving and regulating opening of the MACPF beta-sheet of each new recruit as it adds to the growing pore; and in stabilizing the final pore. Our model of the assembled pore resembles those of the cholesterol-dependent cytolysins (CDCs), but is distinct from that recently proposed for perforin.

Structure of Complement C6 suggests a mechanism for initiation and unidirectional, sequential assembly of the Membrane Attack Complex (MAC).,Aleshin AE, Schraufstatter IU, Stec B, Bankston LA, Liddington RC, Discipio RG J Biol Chem. 2012 Jan 20. PMID:22267737^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.