title: Domain metastability: a molecular basis for immunoglobulin deposition?
abstract: We present the crystal structure of an immunoglobulin light-chain-like domain, CTLA-4, as a strand-swapped dimer displaying cis-trans proline isomerisation and native-like hydrogen bonding. We also show that CTLA-4 can form amyloid-like fibres and amorphous deposits explainable by the same strand swapping. Our results suggest a molecular basis for the pathological aggregation of immunoglobulin domains and why amyloid-like fibres are more often composed of homologous rather than heterologous subunits.
authors.affiliation: Division of Structural Biology, The Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK. andreas@strubi.ox.ac.uk
authors.forename: Andreas F-P
authors.initials: AF
authors.lastname: Sonnen
authors.forename: Chao
authors.initials: C
authors.lastname: Yu
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Evans
authors.forename: David I
authors.initials: DI
authors.lastname: Stuart
authors.forename: Simon J
authors.initials: SJ
authors.lastname: Davis
authors.forename: Robert J C
authors.initials: RJ
authors.lastname: Gilbert
mesh_terms: D000682:Amyloid / Q000737:chemistry / Q000378:metabolism; D015703:Antigens, CD / Q000737:chemistry* / Q000378:metabolism; D060908:CTLA-4 Antigen; D018360:Crystallography, X-Ray; D019281:Dimerization; D006801:Humans; D007147:Immunoglobulin Light Chains / Q000737:chemistry* / Q000378:metabolism; D046911:Macromolecular Substances / Q000737:chemistry; D008854:Microscopy, Electron; D008958:Models, Molecular; D011485:Protein Binding; D020836:Protein Structure, Quaternary; D017434:Protein Structure, Tertiary
chemical_list: D000682:Amyloid; D015703:Antigens, CD; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D007147:Immunoglobulin Light Chains; D046911:Macromolecular Substances
references.citation: Nat Immunol. 2005 Mar;6(3):271-9
references.pmid: 15696168
references.citation: Mol Cell. 2008 Jul 25;31(2):266-77
references.pmid: 18657508
references.citation: Biochemistry. 2002 Apr 9;41(14):4694-703
references.pmid: 11926832
references.citation: Science. 2000 Oct 27;290(5492):816-9
references.pmid: 11052947
references.citation: FEBS Lett. 2004 Apr 23;564(1-2):35-40
references.pmid: 15094039
references.citation: J Neuroimmunol. 2002 Sep;130(1-2):224-32
references.pmid: 12225905
references.citation: J Immunol. 2000 May 15;164(10):5015-8
references.pmid: 10799854
references.citation: Methods Enzymol. 2003;374:300-21
references.pmid: 14696379
references.citation: Acta Crystallogr D Biol Crystallogr. 2007 Jan;63(Pt 1):32-41
references.pmid: 17164524
references.citation: Protein Expr Purif. 1999 Oct;17(1):26-32
references.pmid: 10497065
references.citation: Scand J Immunol. 2003 Jun;57(6):568-72
references.pmid: 12791095
references.citation: Structure. 2006 May;14(5):811-24
references.pmid: 16698543
references.citation: Rheumatology (Oxford). 2004 Oct;43(10):1261-6
references.pmid: 15266059
references.citation: Proc Natl Acad Sci U S A. 2009 May 19;106(20):8198-203
references.pmid: 19416843
references.citation: Nature. 2001 Mar 29;410(6828):608-11
references.pmid: 11279502
references.citation: Biophys J. 2007 Aug 1;93(3):902-13
references.pmid: 17449671
references.citation: Proc Natl Acad Sci U S A. 1999 Mar 30;96(7):3590-4
references.pmid: 10097081
references.citation: Cell Immunol. 2000 May 1;201(2):144-53
references.pmid: 10831323
references.citation: Nat Immunol. 2006 Aug;7(8):803-9
references.pmid: 16855606
references.citation: Proc Natl Acad Sci U S A. 1995 Aug 1;92(16):7337-41
references.pmid: 7638192
references.citation: Nature. 2005 Dec 8;438(7069):878-81
references.pmid: 16341018
references.citation: Nature. 2001 Mar 29;410(6828):604-8
references.pmid: 11279501