CRYSTAL-STRUCTURE OF THE CDK4 6 INHIBITORY PROTEIN P18(INK4C) PROVIDES INSIGHTS INTO ANKYRIN-LIKE REPEAT STRUCTURE/FUNCTION AND TUMOR-DERIVED P16(INK4) MUTATIONS/

p18(INK4c) is, member of a family of INK4 proteins that function to ar rest the G1 to S cell cycle transition by inhibiting the activity of t he cyclin-dependent kinases 4 and 6. The X-ray crystal structure of th e human p18(INK4c) protein to a resolution of 1.95 Angstrom reveals an elongated molecule comprised of five contiguous 32- or 33-residue ank yrin-like repeat units. Each ankyrin-like repeat contains a beta-stran d helix-turn-helix extended strand beta-strand motif that associates w ith neighboring motifs through beta-sheet, and helical bundle interact ions. Conserved ankyrin-like repeat residues function to facilitate th e ankyrin repeat fold and the tertiary interactions between neighborin g repeat units. A large percentage of residues that are conserved amon g INK4 proteins and that map to positions of tumor-derived p16(INK4) m utations play important roles in protein stability. A subset of these residues suggest an INK4 binding surface for the cyclin-dependent kina ses 4 and 6., This surface is centered around a region that shows stru ctural features uncharacteristic of ankyrin-like repeat units.