Crystal structure of the CDK4/6 inhibitory protein p18INK4c provides insights into ankyrin-like repeat structure/function and tumor-derived p16INK4 mutations.
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 A reveals an elongated molecule comprised of five contiguous 32- or 33-residue ankyrin-like repeat units. Each ankyrin-like repeat contains a beta-strand helix-turn-helix extended strand beta-strand motif that associates with neighboring motifs through beta-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.
Venkataramani
R
R
Wistar Institute, Philadelphia, Pennsylvania, USA.
Swaminathan
K
K
Marmorstein
R
R
D000595:Amino Acid Sequence; D017089:Ankyrin Repeat; D002352:Carrier Proteins / Q000648:ultrastructure*; D018797:Cell Cycle Proteins; D016384:Consensus Sequence; D018360:Crystallography, X-Ray; D051361:Cyclin-Dependent Kinase 6; D050763:Cyclin-Dependent Kinase Inhibitor p18; D018844:Cyclin-Dependent Kinases; D004791:Enzyme Inhibitors / Q000737:chemistry*; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009369:Neoplasms / Q000235:genetics; D017354:Point Mutation; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D013329:Structure-Activity Relationship; D025521:Tumor Suppressor Proteins
C493971:CDKN2C protein, human; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D050763:Cyclin-Dependent Kinase Inhibitor p18; D004791:Enzyme Inhibitors; D011994:Recombinant Proteins; D025521:Tumor Suppressor Proteins; D017346:Protein Serine-Threonine Kinases; C495911:CDK6 protein, human; D051361:Cyclin-Dependent Kinase 6; D018844:Cyclin-Dependent Kinases