Determinants of the peptide-induced conformational change in the human class II major histocompatibility complex protein HLA-DR1.
The human class II major histocompatibility complex protein HLA-DR1 has been shown previously to undergo a distinct conformational change from an open to a compact form upon binding peptide. To investigate the role of peptide in triggering the conformational change, the minimal requirements for inducing the compact conformation were determined. Peptides as short as two and four residues, which occupy only a small fraction of the peptide-binding cleft, were able to induce the conformational change. A mutant HLA-DR1 protein with a substitution in the beta subunit designed to fill the P1 pocket from within the protein (Gly(86) to Tyr) adopted to a large extent the compact, peptide-bound conformation. Interactions important in stabilizing the compact conformation are shown to be distinct from those responsible for high affinity binding or for stabilization of the complex against thermal denaturation. The results suggest that occupancy of the P1 pocket is responsible for partial conversion to the compact form but that both side chain and main chain interactions contribute to the full conformational change. The implications of the conformational change to intracellular antigen loading and presentation are discussed.
Sato
A K
AK
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
Zarutskie
J A
JA
Rushe
M M
MM
Lomakin
A
A
Natarajan
S K
SK
Sadegh-Nasseri
S
S
Benedek
G B
GB
Stern
L J
LJ
D000595:Amino Acid Sequence; D002850:Chromatography, Gel; D002942:Circular Dichroism; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D015798:HLA-DR1 Antigen / Q000737:chemistry* / Q000235:genetics*; D000949:Histocompatibility Antigens Class II / Q000737:chemistry*; D006801:Humans; D007700:Kinetics; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016296:Mutagenesis; D010455:Peptides / Q000378:metabolism; D017354:Point Mutation; D011485:Protein Binding; D011487:Protein Conformation; D017510:Protein Folding; D012542:Scattering, Radiation; D013696:Temperature; D013816:Thermodynamics
D015798:HLA-DR1 Antigen; D000949:Histocompatibility Antigens Class II; C024138:I-E-antigen; D010455:Peptides