Membrane pore formation by human complement: Functional importance of the transmembrane beta-hairpin (TMH) segments of C80 alpha and C9

作者：Weiland Mitch H; Qian Yu; Sodetz James M^*

来源：Molecular Immunology, 2014, 57(2): 310-316.

DOI：10.1016/j.molimm.2013.10.007

• Complement
• C8
• C9
• Perfringolysin O
• MACPF
• Membrane attack complex

Human C8 and C9 have a key role in forming the pore-like "membrane attack complex" (MAC) of complement on bacterial cells. A possible mechanism for membrane insertion of these proteins was suggested when studies revealed a structural similarity between the MACPF domains of the C8 alpha and C8 beta subunits and the pore-forming bacterial cholesterol-dependent cytolysins (CDCs). This similarity includes a pair of alpha-helical bundles that in the CDCs refold during pore formation to produce two transmembrane beta-hairpins (TMH1 and TMH2). C9 is the major pore-forming component of the MAC and is also likely to contain two TMH segments because of its homology to C8 alpha and C8 beta. To determine their potential for membrane insertion, the TMH sequences in C8 alpha and those predicted to be in C9 were substituted for the TMH sequences in perfringolysin O (PFO), a well-characterized CDC. Only chimeric proteins containing TMH2 from C8 alpha (PFO/alpha T2) or C9 (PFO/C9T2) could be expressed in soluble, active form. The PFO/alpha T2 and PFO/C9T2 chimeras retained significant hemolytic activity, formed pore-like structures on membranes, and could combine with PFO to form hemolytically active mixed complexes that were functionally similar to PFO alone. These results provide experimental evidence in support of the hypothesis that TMH segments in C8 alpha and those predicted to be in C9 have a direct role in MAC membrane penetration and pore formation.

• 出版日期2014-2