Canonical structures for the hypervariable regions of T cell alpha beta receptors

T cell alpha beta receptors have binding sites for peptide-MHC complexes fo rmed by six hypervariable regions. Analysis of the six atomic structures kn own for V alpha and for V beta domains shows that their first and second hy pervariable regions have one of three or four different main-chain con form ations (canonical structures). Six of these canonical structures have the s ame conformation in complexes with peptide-MHC complexes, the free receptor and/or in an isolated V domain. Thus, for at least the first and second hy pervariable regions in the currently known structures, the conformation of the canonical structures is well defined in the free state and is conserved on formation of complexes with peptide-MHC. We identified the key residues that are mainly responsible for the con form ation of each canonical structure. The first and second hypervariable regio ns of V alpha and V beta domains are encoded by the germline V segments. Hu mans have 37 functional V alpha segments and 47 V beta segments, and mice h ave 20 V beta segments. Inspection of the size of their hypervariable regio ns, and of sites that contain key residues, indicates that close to 70% of V alpha segments and 90% of V beta segments have hypervariable regions with a conformation of one of the known canonical structures. The alpha and bet a V gene segments in both humans and mice have only a few combinations of d ifferent canonical structure in their first and second hypervariable region s. Ln human V beta domains, the number of different sequences with these ca nonical structure combinations is larger than in mice, whilst for V alpha d omains it is probably smaller. (C) 2000 Academic Press.