title: Conformational lability in the class II MHC 310 helix and adjacent extended strand dictate HLA-DM susceptibility and peptide exchange.
abstract: HLA-DM is required for efficient peptide exchange on class II MHC molecules, but its mechanism of action is controversial. We trapped an intermediate state of class II MHC HLA-DR1 by substitution of αF54, resulting in a protein with increased HLA-DM binding affinity, weakened MHC-peptide hydrogen bonding as measured by hydrogen-deuterium exchange mass spectrometry, and increased susceptibility to DM-mediated peptide exchange. Structural analysis revealed a set of concerted conformational alterations at the N-terminal end of the peptide-binding site. These results suggest that interaction with HLA-DM is driven by a conformational change of the MHC II protein in the region of the α-subunit 3(10) helix and adjacent extended strand region, and provide a model for the mechanism of DM-mediated peptide exchange.
authors.affiliation: Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, MA 10655, USA.
authors.forename: Corrie A
authors.initials: CA
authors.lastname: Painter
authors.forename: Maria P
authors.initials: MP
authors.lastname: Negroni
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Kellersberger
authors.forename: Zarixia
authors.initials: Z
authors.lastname: Zavala-Ruiz
authors.forename: James E
authors.initials: JE
authors.lastname: Evans
authors.forename: Lawrence J
authors.initials: LJ
authors.lastname: Stern
mesh_terms: D000818:Animals; D017951:Antigen Presentation / Q000276:immunology*; D002846:Chromatography, Affinity; D002850:Chromatography, Gel; D003461:Crystallography; D004330:Drosophila; D004926:Escherichia coli; D005453:Fluorescence; D006681:HLA-D Antigens / Q000378:metabolism*; D015798:HLA-DR1 Antigen / Q000737:chemistry / Q000378:metabolism*; D006860:Hydrogen Bonding; D013058:Mass Spectrometry / Q000379:methods; D008958:Models, Molecular; D010455:Peptides / Q000378:metabolism*; D011487:Protein Conformation; D017510:Protein Folding; D020349:Surface Plasmon Resonance
chemical_list: D006681:HLA-D Antigens; C084245:HLA-DM antigens; D015798:HLA-DR1 Antigen; D010455:Peptides
references.citation: J Exp Med. 2000 Dec 18;192(12):1697-706
references.pmid: 11120767
references.citation: J Immunol. 2002 Nov 1;169(9):5109-17
references.pmid: 12391227
references.citation: PLoS One. 2008 Jun 11;3(6):e2403
references.pmid: 18545669
references.citation: J Biol Chem. 2000 Jan 21;275(3):2165-73
references.pmid: 10636922
references.citation: J Immunol. 1999 Oct 1;163(7):3567-71
references.pmid: 10490947
references.citation: Cell. 1995 Jul 14;82(1):155-65
references.pmid: 7606781
references.citation: J Biol Chem. 1998 Oct 16;273(42):27557-64
references.pmid: 9765288
references.citation: Immunity. 2003 Aug;19(2):183-92
references.pmid: 12932352
references.citation: Acta Crystallogr D Biol Crystallogr. 2010 Feb;66(Pt 2):213-21
references.pmid: 20124702
references.citation: Proc Natl Acad Sci U S A. 2001 Oct 23;98(22):12450-5
references.pmid: 11606721
references.citation: Nat Immunol. 2011 Jan;12(1):54-61
references.pmid: 21131964
references.citation: Science. 1996 Oct 25;274(5287):618-20
references.pmid: 8849454
references.citation: Nat Immunol. 2007 Jan;8(1):92-100
references.pmid: 17143275
references.citation: Immunity. 2000 Oct;13(4):517-27
references.pmid: 11070170
references.citation: Biopolymers. 2009 Jan;91(1):14-27
references.pmid: 18767126
references.citation: Anal Chem. 2009 Jul 15;81(14):5577-84
references.pmid: 19601649
references.citation: J Immunol. 2010 Feb 1;184(3):1153-8
references.pmid: 20038641
references.citation: J Immunol Methods. 2002 May 1;263(1-2):111-21
references.pmid: 12009208
references.citation: J Leukoc Biol. 2008 Oct;84(4):1011-8
references.pmid: 18591414
references.citation: J Exp Med. 1996 Dec 1;184(6):2153-65
references.pmid: 8976171
references.citation: J Immunol. 2004 Jan 15;172(2):1109-17
references.pmid: 14707085
references.citation: J Immunol. 2003 Sep 1;171(5):2183-6
references.pmid: 12928360
references.citation: Curr Med Chem. 2007;14(22):2344-58
references.pmid: 17896983
references.citation: PLoS One. 2011 Apr 14;6(4):e18662
references.pmid: 21533180
references.citation: Immunity. 1997 Mar;6(3):293-302
references.pmid: 9075930
references.citation: J Exp Med. 2002 Jul 15;196(2):173-83
references.pmid: 12119342
references.citation: Biochim Biophys Acta. 2006 Dec;1764(12):1811-22
references.pmid: 17118725
references.citation: PLoS One. 2008;3(11):e3722
references.pmid: 19005572
references.citation: Nature. 1995 Jun 29;375(6534):802-6
references.pmid: 7596415
references.citation: Mol Immunol. 2008 Feb;45(4):1063-70
references.pmid: 17870168
references.citation: Nature. 1994 Apr 7;368(6471):551-4
references.pmid: 8139689
references.citation: Proc Natl Acad Sci U S A. 1988 Jun;85(11):3975-9
references.pmid: 3287381
references.citation: J Exp Med. 2006 May 15;203(5):1319-28
references.pmid: 16682499
references.citation: EMBO J. 1996 Nov 15;15(22):6144-54
references.pmid: 8947036
references.citation: Acta Crystallogr D Biol Crystallogr. 2004 Dec;60(Pt 12 Pt 1):2126-32
references.pmid: 15572765
references.citation: J Appl Crystallogr. 2007 Aug 1;40(Pt 4):658-674
references.pmid: 19461840
references.citation: Biochemistry. 1999 May 4;38(18):5878-87
references.pmid: 10231540
references.citation: J Immunol. 2009 Oct 1;183(7):4187-91
references.pmid: 19767569
references.citation: Proc Natl Acad Sci U S A. 1997 Nov 25;94(24):13163-8
references.pmid: 9371817
references.citation: Protein Expr Purif. 1999 Feb;15(1):105-14
references.pmid: 10024477