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Crystal structure of the CDK4/6 inhibitory protein p18INK4c provides insights into ankyrin-like repeat structure/function and tumor-derived p16INK4 mutations

Nature Structural Biology volume 5, pages 74–81 (1998)Cite this article

Abstract

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 β-strand helix-turn-helix extended strand β-strand motif that associates with neighboring motifs through β-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.

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Author notes

  1. Kunchithapadam Swaminathan

    Present address: Institute of Molecular Agrobiology, National University of Singapore, 118240, Singapore

Authors and Affiliations

  1. The Wistar Institute, University of Pennsylvania, Philadelphia, Pennsylvania, 19104, USA

    Ravichandran Venkataramani, Kunchithapadam Swaminathan & Ronen Marmorstein

  2. Department of Biochemistry and Biophysics, University of Pennsylvania, Philadelphia, Pennsylvania, 19104, USA

    Ravichandran Venkataramani & Ronen Marmorstein

  3. Department of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania, 19104, USA

    Ronen Marmorstein

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  1. Ravichandran Venkataramani
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Correspondence to Ronen Marmorstein.

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Venkataramani, R., Swaminathan, K. & Marmorstein, R. Crystal structure of the CDK4/6 inhibitory protein p18INK4c provides insights into ankyrin-like repeat structure/function and tumor-derived p16INK4 mutations. Nat Struct Mol Biol 5, 74–81 (1998). https://doi.org/10.1038/nsb0198-74

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