The structure and stability of an HLA-A*0201/octameric tax peptide complex with an empty conserved peptide-N-terminal binding site.
The crystal structure of the human class I MHC molecule HLA-A2 complexed with of an octameric peptide, Tax8 (LFGYPVYV), from human T cell lymphotrophic virus-1 (HTLV-1) has been determined. This structure is compared with a newly refined, higher resolution (1.8 A) structure of HLA-A2 complexed with the nonameric Tax9 peptide (LLFGYPVYV) with one more N-terminal residue. Despite the absence of a peptide residue (P1) bound in the conserved N-terminal peptide-binding pocket of the Tax8/HLA-A2 complex, the structures of the two complexes are essentially identical. Water molecules in the Tax8 complex replace the terminal amino group of the Tax9 peptide and mediate a network of hydrogen bonds among the secondary structural elements at that end of the peptide-binding groove. Thermal denaturation measurements indicate that the Tax8 complex is much less stable, DeltaTm = 16 degrees C, than the Tax9 complex, but both can sensitize target cells for lysis by some Tax-specific CTL from HTLV-1 infected individuals. The absence of a P1 peptide residue is thus not enough to prevent formation of a "closed conformation" of the peptide-binding site. TCR affinity measurements and cytotoxic T cell assays indicate that the Tax8/HLA-A2 complex does not functionally cross-react with the A6-TCR-bearing T cell clone specific for Tax9/HLA-A2 complexes.
Khan
A R
AR
Department of Molecular and Cellular Biology and Howard Hughes Medical Institute, Harvard University, Cambridge MA 02138, USA.
Baker
B M
BM
Ghosh
P
P
Biddison
W E
WE
Wiley
D C
DC
D001665:Binding Sites / Q000276:immunology; D002999:Clone Cells; D017124:Conserved Sequence; D018360:Crystallography, X-Ray; D003601:Cytotoxicity Tests, Immunologic; D016356:Gene Products, tax / Q000737:chemistry* / Q000378:metabolism; D015789:HLA-A2 Antigen / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D008213:Lymphocyte Activation; D046911:Macromolecular Substances; D009842:Oligopeptides / Q000737:chemistry* / Q000378:metabolism; D010446:Peptide Fragments / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D012997:Solvents; D013329:Structure-Activity Relationship; D013602:T-Lymphocytes, Cytotoxic / Q000378:metabolism; D013816:Thermodynamics; D014867:Water
D016356:Gene Products, tax; D015789:HLA-A2 Antigen; D046911:Macromolecular Substances; D009842:Oligopeptides; D010446:Peptide Fragments; D011948:Receptors, Antigen, T-Cell; D012997:Solvents; D014867:Water