3t5o

Crystal Structure of human Complement Component C6

spinqualitylabelsall models 3t5o, resolution 2.87Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 3t5o is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.869Å Ligands: BGC, CD, FUC, FUL, MAN, NAG Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease CO6_HUMAN Defects in C6 are the cause of complement component 6 deficiency (C6D) [MIM:612446. A rare defect of the complement classical pathway associated with susceptibility to severe recurrent infections, predominantly by Neisseria gonorrhoeae or Neisseria meningitidis. Function CO6_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. 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 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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