Molecular basis for unidirectional scaffold switching of human Plk4 in centriole biogenesis

Nat Struct Mol Biol. 2014 Aug;21(8):696-703. doi: 10.1038/nsmb.2846. Epub 2014 Jun 29.

Abstract

Polo-like kinase 4 (Plk4) is a key regulator of centriole duplication, an event critical for the maintenance of genomic integrity. We show that Plk4 relocalizes from the inner Cep192 ring to the outer Cep152 ring as newly recruited Cep152 assembles around the Cep192-encircled daughter centriole. Crystal-structure analyses revealed that Cep192- and Cep152-derived peptides bind the cryptic polo box (CPB) of Plk4 in opposite orientations and in a mutually exclusive manner. The Cep152 peptide bound to the CPB markedly better than did the Cep192 peptide and effectively 'snatched' the CPB away from a preformed CPB-Cep192 peptide complex. A cancer-associated Cep152 mutation impairing the Plk4 interaction induced defects in procentriole assembly and chromosome segregation. Thus, Plk4 is intricately regulated in time and space through ordered interactions with two distinct scaffolds, Cep192 and Cep152, and a failure in this process may lead to human cancer.

Publication types

  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Cell Cycle Proteins / chemistry*
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism
  • Centrioles / metabolism*
  • Chromosomal Proteins, Non-Histone / chemistry*
  • Chromosomal Proteins, Non-Histone / metabolism
  • Crystallography, X-Ray
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Hydrogen Bonding
  • Models, Molecular
  • Molecular Sequence Data
  • Mutation, Missense
  • Neoplasms / genetics
  • Protein Binding
  • Protein Interaction Domains and Motifs
  • Protein Structure, Quaternary
  • Protein Structure, Secondary
  • Protein-Serine-Threonine Kinases / chemistry*
  • Protein-Serine-Threonine Kinases / metabolism

Substances

  • CEP152 protein, human
  • Cell Cycle Proteins
  • Cep192 protein, human
  • Chromosomal Proteins, Non-Histone
  • PLK4 protein, human
  • Protein-Serine-Threonine Kinases

Associated data

  • PDB/4N7V
  • PDB/4N7Z
  • PDB/4N9J