HLA-DM captures partially empty HLA-DR molecules for catalyzed removal of peptide.
The mechanisms of HLA-DM-catalyzed peptide exchange remain uncertain. Here we found that all stages of the interaction of HLA-DM with HLA-DR were dependent on the occupancy state of the peptide-binding groove. High-affinity peptides were protected from removal by HLA-DM through two mechanisms: peptide binding induced the dissociation of a long-lived complex of empty HLA-DR and HLA-DM, and high-affinity HLA-DR-peptide complexes bound HLA-DM only very slowly. Nonbinding covalent HLA-DR-peptide complexes were converted into efficient HLA-DM binders after truncation of an N-terminal peptide segment that emptied the P1 pocket and disrupted conserved hydrogen bonds to HLA-DR. HLA-DM thus binds only to HLA-DR conformers in which a critical part of the binding site is already vacant because of spontaneous peptide motion.
Department of Cancer Immunology & AIDS, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.
Anne-Kathrin
AK
Anders
Melissa J
MJ
Call
Monika-Sarah E D
MS
Schulze
Kevin D
KD
Fowler
David A
DA
Schubert
Nilufer P
NP
Seth
Eric J
EJ
Sundberg
Kai W
KW
Wucherpfennig
D000818:Animals; D017951:Antigen Presentation; D016466:CHO Cells; D002384:Catalysis; D006224:Cricetinae; D003412:Cricetulus; D006681:HLA-D Antigens / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015802:HLA-DR2 Antigen / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008956:Models, Chemical; D016297:Mutagenesis, Site-Directed; D050505:Mutant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D010446:Peptide Fragments / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D020349:Surface Plasmon Resonance; D019076:Transgenes / Q000235:genetics
D006681:HLA-D Antigens; C084245:HLA-DM antigens; D015802:HLA-DR2 Antigen; D050505:Mutant Proteins; D010446:Peptide Fragments