Arvai A S, Bourne Y, Hickey M J, Tainer J A
Department of Molecular Biology, Scripps Research Institute, La Jolla, CA 92037, USA.
J Mol Biol. 1995 Jun 23;249(5):835-42. doi: 10.1006/jmbi.1995.0341.
The structure of the human CksHs1 homolog of the yeast cell-cycle regulatory proteins suc1 and CKS1, which bind to the catalytic subunit of the cyclin-dependent kinases (Cdks) and are essential for yeast cell-cycle progression in vivo, has been determined at 2.9 A resolution. The CksHs1 single polypeptide domain fold, which consists of a four-stranded beta-sheet flanked by two alpha-helices, is dramatically different from the subunit conformation and assembly of the homologous CksHs2, but strikingly similar to the Cdk N-lobe domain fold. The CksHs1 structure identifies sequence-conserved residues Glu61 to His65 as a novel beta-hinge region that folds back to form a beta-hairpin with CksHs1 subunit, whereas this hinge is unfolded to form an extended beta-strand exchange between two CksHs2 subunits. Phosphate and the phosphate analog metavanadate bind CksHs1 in a shallow pocket and interact with five conserved residues (Lys11, Arg20, Ser51, Trp54 and Arg71) suggesting a specific Cks recognition site for a phosphorylated Cdk residue. The dramatic changes to the Cks fold, assembly and exposed conserved surface brought about by switching between the bent and extended hinge conformations are potentially important for the functions of this Cks homolog and could explain conflicting activities inferred from different types of genetic experiments.
酵母细胞周期调节蛋白suc1和CKS1的人类同源物CksHs1的结构已在2.9埃分辨率下确定。suc1和CKS1可与细胞周期蛋白依赖性激酶（Cdk）的催化亚基结合，对酵母体内细胞周期进程至关重要。CksHs1单多肽结构域折叠由一个四链β折叠片组成，两侧为两个α螺旋，与同源的CksHs2的亚基构象和组装显著不同，但与Cdk N叶结构域折叠惊人地相似。CksHs1结构将序列保守的Glu61至His65残基确定为一个新的β铰链区，该区域向后折叠与CksHs1亚基形成一个β发夹，而在两个CksHs2亚基之间，这个铰链展开形成一个延伸的β链交换。磷酸盐和磷酸盐类似物偏钒酸盐在一个浅口袋中结合CksHs1，并与五个保守残基（Lys11、Arg20、Ser51、Trp54和Arg71）相互作用，表明存在一个针对磷酸化Cdk残基的特定Cks识别位点。在弯曲和延伸的铰链构象之间切换所带来的Cks折叠、组装和暴露的保守表面的显著变化，可能对该Cks同源物的功能具有重要意义，并可以解释从不同类型的遗传实验中推断出的相互矛盾活动。
