CRYSTAL-STRUCTURE OF THE HUMAN CELL-CYCLE PROTEIN CKSHS1 - SINGLE-DOMAIN FOLD WITH SIMILARITY TO KINASE N-LOBE DOMAIN

The structure of the human CksHs1 homolog of the yeast cell-cycle regu latory proteins suc1 and CKS1, which bind to the catalytic subunit of the cyclin-dependent kinases (Cdks) and are essential for yeast cell-c ycle progression in vivo, has been determined at 2.9 Angstrom resoluti on. The CksHs1 single polypeptide domain fold, which consists of a fou r-stranded beta-sheet flanked by two alpha-helices, is dramatically di fferent from the subunit conformation and assembly of the homologous C ksHs2, but strikingly similar to the Cdk N-lobe domain fold. The CksHs 1 structure identifies sequence-conserved residues Glu61 to His65 as a novel beta-hinge region that folds back to form a beta-hairpin with C ksHs1 subunit, whereas this hinge is unfolded to form an extended beta -strand exchange between two CksHs2 subunits. Phosphate and the phosph ate analog metavanadate bind CksHs1 in a shallow pocket and interact w ith five conserved residues (Lys11, Arg20, Ser51, Trp54 and Arg71) sug gesting a specific Cks recognition site for a phosphorylated Cdk resid ue. The dramatic changes to the Cks fold, assembly and exposed conserv ed surface brought about by switching between the bent and extended hi nge conformations are potentially important for the functions of this Cks homolog and could explain conflicting activities inferred from dif ferent types of genetic experiments.