Crystal structure of the MACPF domain of human complement protein C8 alpha in complex with the C8 gamma subunit

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dc.contributor.authorSlade, Daniel J.en
dc.contributor.authorLovelace, Leslie L.en
dc.contributor.authorChruszcz, Maksymilianen
dc.contributor.authorMinor, Wladeken
dc.contributor.authorLebioda, Lukaszen
dc.contributor.authorSodetz, James M.en
dc.contributor.departmentBiochemistryen
dc.contributor.departmentCenter for Drug Discoveryen
dc.date.accessioned2016-11-09T03:23:17Zen
dc.date.available2016-11-09T03:23:17Zen
dc.date.issued2008-05-29en
dc.description.abstractHuman C8 is one of five complement components (C5b, C6, C7, C8 and C9) that assemble on bacterial membranes to form a pore-like structure referred to as the "membrane attack complex" (MAC). C8 contains three genetically distinct subunits (C8α, C8β, Cγ.) arranged as a disulfide-linked C8α-γ dimer that is noncovalently associated with C8β. C6, C7 C8α, C8β and C9 are homologous. All contain N- and C-terminal modules and an intervening 40-kDa segment referred to as the membrane attack complex/perforin (MACPF) domain. The C8γ subunit is unrelated and belongs to the lipocalin family of proteins that display a β-barrel fold and generally bind small, hydrophobic ligands. Several hundred proteins with MACPF domains have been identified based on sequence similarity; however, the structure and function of most are unknown. Crystal structures of the secreted bacterial protein Plu-MACPF and the human C8α MACPF domain were recently reported and both display a fold similar to the bacterial pore-forming cholesterol-dependent cytolysins (CDC). In the present study, we determined the crystal structure of the human C8α MACPF domain disulfide-linked to C8γ (αMACPF-γ) at 2.15 Å resolution. The αMACPF portion has the predicted CDC-like fold and shows two regions of interaction with C8γ. One is in a previously characterized 19-residue insertion (indel) in C8α and fills the entrance to the putative C8γ ligand binding site. The second is a hydrophobic pocket that makes contact with residues on the side of the C8γ β-barrel. The latter interaction induces conformational changes in αMACPF that are likely important for C8 function. Also observed is structural conservation of the MACPF signature motif Y/W-G-T/S-H-F/Y-X6-G-G in αMACPF and Plu-MACPF, and conservation of several key glycine residues known to be important for refolding and pore formation by CDCs.en
dc.description.versionPublished versionen
dc.format.extent331 - 342 (12) page(s)en
dc.identifier.doihttps://doi.org/10.1016/j.jmb.2008.03.061en
dc.identifier.issn0022-2836en
dc.identifier.issue2en
dc.identifier.urihttp://hdl.handle.net/10919/73411en
dc.identifier.volume379en
dc.language.isoenen
dc.publisherAcademic Press – Elsevieren
dc.relation.urihttp://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000256328300011&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=930d57c9ac61a043676db62af60056c1en
dc.rightsIn Copyrighten
dc.rights.urihttp://rightsstatements.org/vocab/InC/1.0/en
dc.subjectBiochemistry & Molecular Biologyen
dc.subjectcomplementen
dc.subjectMACPFen
dc.subjectC8en
dc.subjectcytolysinsen
dc.subjectmembrane attack complexen
dc.subjectMEMBRANE ATTACK COMPLEXen
dc.subjectCHOLESTEROL-DEPENDENT CYTOLYSINen
dc.subjectLIGAND-BINDING SITEen
dc.subjectPORE-FORMING TOXINSen
dc.subjectMOLECULAR GRAPHICSen
dc.subjectPERFRINGOLYSIN Oen
dc.subject8TH COMPONENTen
dc.subjectCELL-DEATHen
dc.subjectMODELen
dc.titleCrystal structure of the MACPF domain of human complement protein C8 alpha in complex with the C8 gamma subuniten
dc.title.serialJournal of Molecular Biologyen
dc.typeArticle - Refereeden
dc.type.dcmitypeTexten
pubs.organisational-group/Virginia Techen
pubs.organisational-group/Virginia Tech/Agriculture & Life Sciencesen
pubs.organisational-group/Virginia Tech/Agriculture & Life Sciences/Biochemistryen
pubs.organisational-group/Virginia Tech/Agriculture & Life Sciences/CALS T&R Facultyen
pubs.organisational-group/Virginia Tech/All T&R Facultyen
pubs.organisational-group/Virginia Tech/Faculty of Health Sciencesen

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