Home LiteratureArticle Details
PMID: 11606721 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

The kinetic basis of peptide exchange catalysis by HLA-DM.

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 98 ·No. 22 ·2001-10-23 ·Pages 12450-5

Zarutskie JA, Busch R, Zavala-Ruiz Z, Rushe M, Mellins ED, Stern LJ

Abstract

The mechanism by which the peptide exchange factor HLA-DM catalyzes peptide loading onto structurally homologous class II MHC proteins is an outstanding problem in antigen presentation. The peptide-loading reaction of class II MHC proteins is complex and includes conformational changes in both empty and peptide-bound forms in addition to a bimolecular binding step. By using a fluorescence energy transfer assay to follow the kinetics of peptide binding to the human class II MHC protein HLA-DR1, we find that HLA-DM catalyzes peptide exchange by facilitating a conformational change in the peptide-bound complex, and not by promoting the bimolecular MHC-peptide reaction or the conversion between peptide-receptive and -averse forms of the empty protein. Thus, HLA-DM serves essentially as a protein-folding or conformational catalyst.

MeSH Terms
Antigens, Differentiation, B-Lymphocyte/metabolism Catalysis HLA-D Antigens/pharmacology HLA-DR1 Antigen/metabolism Hemagglutinin Glycoproteins, Influenza Virus/metabolism Histocompatibility Antigens Class II/metabolism Kinetics Protein Conformation Protein Folding
Chemicals
Antigens, Differentiation, B-Lymphocyte HLA-D Antigens HLA-DM antigens HLA-DR1 Antigen Hemagglutinin Glycoproteins, Influenza Virus Histocompatibility Antigens Class II invariant chain
Authors & Affiliations
6 authors, click to expand affiliations / ORCID
Zarutskie J A
Department of Chemistry, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA.
Busch R
Zavala-Ruiz Z
Rushe M
Mellins E D
Stern L J
References (35)
35 references, click to expand
  1. Empty and peptide-loaded class II major histocompatibility complex proteins produced by expression in Escherichia coli and folding in vitro.
    Protein Expr Purif. 1999 Feb;15(1):105-14 PMID: 10024477
  2. Stable peptide binding to MHC class II molecule is rapid and is determined by a receptive conformation shaped by prior association with low affinity peptides.
    J Immunol. 1999 Apr 1;162(7):4030-6 PMID: 10201925
  3. A conformational change in the human major histocompatibility complex protein HLA-DR1 induced by peptide binding.
    Biochemistry. 1999 May 4;38(18):5878-87 PMID: 10231540
  4. Ovalbumin(323-339) peptide binds to the major histocompatibility complex class II I-A(d) protein using two functionally distinct registers.
    Biochemistry. 1999 Dec 14;38(50):16663-70 PMID: 10600129
  5. Determinants of the peptide-induced conformational change in the human class II major histocompatibility complex protein HLA-DR1.
    J Biol Chem. 2000 Jan 21;275(3):2165-73 PMID: 10636922
  6. Kinetics of peptide binding to the class II MHC protein I-Ek.
    Biochemistry. 2000 Feb 8;39(5):1048-58 PMID: 10653650
  7. A three-step kinetic mechanism for peptide binding to MHC class II proteins.
    Biochemistry. 2000 Apr 4;39(13):3751-62 PMID: 10736175
  8. Determination of the HLA-DM interaction site on HLA-DR molecules.
    Immunity. 2000 Oct;13(4):517-27 PMID: 11070170
  9. HLA-DM recognizes the flexible conformation of major histocompatibility complex class II.
    J Exp Med. 2000 Dec 18;192(12):1697-706 PMID: 11120767
  10. The human class II MHC protein HLA-DR1 assembles as empty alpha beta heterodimers in the absence of antigenic peptide.
    Cell. 1992 Feb 7;68(3):465-77 PMID: 1371238
  11. HLA-DR molecules from an antigen-processing mutant cell line are associated with invariant chain peptides.
    Nature. 1992 Dec 3;360(6403):474-7 PMID: 1448172
  12. Invariant chain peptides in most HLA-DR molecules of an antigen-processing mutant.
    Science. 1992 Dec 11;258(5089):1801-4 PMID: 1465617
  13. Proteolysis of the class II-associated invariant chain generates a peptide binding site in intracellular HLA-DR molecules.
    Proc Natl Acad Sci U S A. 1991 Apr 15;88(8):3150-4 PMID: 2014234
  14. High-affinity binding of an influenza hemagglutinin-derived peptide to purified HLA-DR.
    J Immunol. 1990 Mar 1;144(5):1849-56 PMID: 2307844
  15. A kinetic intermediate in the reaction of an antigenic peptide and I-Ek.
    Nature. 1989 Jan 19;337(6204):274-6 PMID: 2536141
  16. Interaction between a "processed" ovalbumin peptide and Ia molecules.
    Proc Natl Acad Sci U S A. 1986 Jun;83(11):3968-71 PMID: 3487084
  17. Mediation by HLA-DM of dissociation of peptides from HLA-DR.
    Nature. 1995 Jun 29;375(6534):802-6 PMID: 7596415
  18. MHC class II function preserved by low-affinity peptide interactions preceding stable binding.
    Nature. 1994 Aug 25;370(6491):647-50 PMID: 8065450
  19. Kinetic intermediates in the reactions between peptides and proteins of major histocompatibility complex class II.
    Proc Natl Acad Sci U S A. 1994 Sep 13;91(19):8842-5 PMID: 8090733
  20. An essential role for HLA-DM in antigen presentation by class II major histocompatibility molecules.
    Nature. 1994 Apr 7;368(6471):551-4 PMID: 8139689
  21. HLA-DMA and -DMB genes are both required for MHC class II/peptide complex formation in antigen-presenting cells.
    Nature. 1994 Apr 7;368(6471):554-8 PMID: 8139690
  22. MHC-dependent antigen processing and peptide presentation: providing ligands for T lymphocyte activation.
    Cell. 1994 Jan 28;76(2):287-99 PMID: 8293464
  23. Kinetic analysis of peptide loading onto HLA-DR molecules mediated by HLA-DM.
    Proc Natl Acad Sci U S A. 1996 Sep 3;93(18):9724-9 PMID: 8790398
  24. Enhanced dissociation of HLA-DR-bound peptides in the presence of HLA-DM.
    Science. 1996 Oct 25;274(5287):618-20 PMID: 8849454
  25. Editing of the HLA-DR-peptide repertoire by HLA-DM.
    EMBO J. 1996 Nov 15;15(22):6144-54 PMID: 8947036
  26. HLA-DM interactions with intermediates in HLA-DR maturation and a role for HLA-DM in stabilizing empty HLA-DR molecules.
    J Exp Med. 1996 Dec 1;184(6):2153-65 PMID: 8976171
  27. How HLA-DM edits the MHC class II peptide repertoire: survival of the fittest?
    Immunol Today. 1997 Feb;18(2):77-82 PMID: 9057358
  28. HLA-DM acts as a molecular chaperone and rescues empty HLA-DR molecules at lysosomal pH.
    Immunity. 1997 Mar;6(3):293-302 PMID: 9075930
  29. Capture and processing of exogenous antigens for presentation on MHC molecules.
    Annu Rev Immunol. 1997;15:821-50 PMID: 9143708
  30. Secondary structure composition and pH-dependent conformational changes of soluble recombinant HLA-DM.
    J Biol Chem. 1998 Oct 16;273(42):27557-64 PMID: 9765288
  31. The structure of HLA-DM, the peptide exchange catalyst that loads antigen onto class II MHC molecules during antigen presentation.
    Immunity. 1998 Sep;9(3):377-83 PMID: 9768757
  32. Crystal structure of mouse H2-M.
    Immunity. 1998 Sep;9(3):385-93 PMID: 9768758
  33. Formation of a highly peptide-receptive state of class II MHC.
    Immunity. 1998 Nov;9(5):699-709 PMID: 9846491
  34. Kinetic isomers of a class II MHC-peptide complex.
    Biochemistry. 1998 Dec 15;37(50):17371-80 PMID: 9860852
  35. Conformational isomers of a class II MHC-peptide complex in solution.
    J Mol Biol. 1999 Feb 12;286(1):207-18 PMID: 9931260
Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
0027-8424
DOI
10.1073/pnas.211439398
Published
2001-10-23
Epub
2001-00-16
Pages
12450-5
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC60074
Subset
IM
Grants
NIAID NIH HHS · R01 AI038996 · United States
NIAID NIH HHS · R01-AI28809 · United States
NIAID NIH HHS · R01-AI38996 · United States
External Links
PubMed source DOI: 10.1073/pnas.211439398 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: [email protected]

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2