Functional studies of the MACPF domain of human complement protein C8alpha reveal sites for simultaneous binding of C8beta, C8gamma, and C9

Biochemistry
Daniel J SladeJ M Sodetz

Abstract

Human C8 is one of five components of the membrane attack complex of complement (MAC). It contains three subunits (C8alpha, C8beta, C8gamma) arranged as a disulfide-linked C8alpha-gamma dimer that is noncovalently associated with C8beta. C8alpha, C8beta, and complement components C6, C7, and C9 form the MAC family of proteins. All contain N- and C-terminal modules and an intervening 40-kDa segment referred to as the membrane attack complex/perforin (MACPF) domain. During MAC formation, C8alpha binds and mediates the self-polymerization of C9 to form a pore-like structure on target cells. The C9 binding site was previously shown to reside within a 52-kDa segment composed of the C8alpha N-terminal modules and MACPF domain (alphaMACPF). In the present study, we examined the role of the MACPF domain in binding C9. Recombinant alphaMACPF and a disulfide-linked alphaMACPF-gamma dimer were successfully produced in Escherichia coli and purified. alphaMACPF was shown to simultaneously bind C8beta, C8gamma, and C9 and form a noncovalent alphaMACPF.C8beta.C8gamma.C9 complex. Similar results were obtained for the recombinant alphaMACPF-gamma dimer. This dimer bound C8beta and C9 to form a hemolytically active (alphaMACPF-gamma).C8beta.C9 c...Continue Reading

References

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Citations

Dec 3, 2008·Journal of Molecular Modeling·Athanassios Stavrakoudis
Apr 2, 2011·The Journal of Biological Chemistry·Leslie L LovelaceLukasz Lebioda
Feb 5, 2016·Nature Communications·Marina SernaDoryen Bubeck
Jun 10, 2011·Comparative Biochemistry and Physiology. Part D, Genomics & Proteomics·Changlu LiNing Li
Nov 16, 2010·Journal of Molecular Biology·Doryen BubeckSusan M Lea
Jun 26, 2017·Seminars in Cell & Developmental Biology·B Paul MorganDoryen Bubeck
Jun 20, 2008·Cellular Microbiology·Carlos J RosadoMichelle A Dunstone

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