Crystal structure of the CDK4/6 inhibitory protein p18INK4c provides insights into ankyrin-like repeat structure/function and tumor-derived p16INK4 mutations
1The Wistar Institute, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
2Department of Biochemistry and Biophysics, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
3Department of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
4Current address: Institute of Molecular Agrobiology, National University of Singapore, Singapore, 118240
5e-mail: marmor@wista.wistar.upenn.edu.
p18INK4c is a member of a family of INK4 proteins that function to arrest the G1 to S cell cycle transition by inhibiting the activity of the cyclin-dependent kinases 4 and 6. The X-ray crystal structure of the human p18INK4c protein to a resolution of 1.95 Å reveals an elongated molecule comprised of five contiguous 32- or 33-residue ankyrin-like repeat units. Each ankyrin-like repeat contains a -strand helix-turn-helix extended strand -strand motif that associates with neighboring motifs through -sheet, and helical bundle interactions. Conserved ankyrin-like repeat residues function to facilitate the ankyrin repeat fold and the tertiary interactions between neighboring repeat units. A large percentage of residues that are conserved among INK4 proteins and that map to positions of tumor-derived p16INK4 mutations play important roles in protein stability. A subset of these residues suggest an INK4 binding surface for the cyclin-dependent kinases 4 and 6. This surface is centered around a region that shows structural features uncharacteristic of ankyrin-like repeat units.
-strand helix-turn-helix extended strand 
