The kinetic basis of peptide exchange catalysis by HLA-DM.
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.
Zarutskie
J A
JA
Department of Chemistry, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA.
Busch
R
R
Zavala-Ruiz
Z
Z
Rushe
M
M
Mellins
E D
ED
Stern
L J
LJ
D000944:Antigens, Differentiation, B-Lymphocyte / Q000378:metabolism; D002384:Catalysis; D006681:HLA-D Antigens / Q000494:pharmacology*; D015798:HLA-DR1 Antigen / Q000378:metabolism; D019267:Hemagglutinin Glycoproteins, Influenza Virus / Q000378:metabolism; D000949:Histocompatibility Antigens Class II / Q000378:metabolism; D007700:Kinetics; D011487:Protein Conformation; D017510:Protein Folding
D000944:Antigens, Differentiation, B-Lymphocyte; D006681:HLA-D Antigens; C084245:HLA-DM antigens; D015798:HLA-DR1 Antigen; D019267:Hemagglutinin Glycoproteins, Influenza Virus; D000949:Histocompatibility Antigens Class II; C045084:invariant chain