Direct binding of CEP85 to STIL ensures robust PLK4 activation and efficient centriole assembly

• DOI: 10.1038/s41467-018-04122-x
• Publication Date: 2018-04-24T14:37:58Z
• Authors: Yi Liu; Gagan D. Gupta; Deepak D. Barnabas; Fikret G. Agircan; Shahid Mehmood; Di Wu; Etienne Coyaud; Christopher M. Jo...; Stephen H. McLaug...; Antonina Andreeva; Stefan M. V. Freund; Carol V. Robinson; Sally W. T. Cheung; Brian Raught; Laurence Pelletier; Mark van Breugel
• Keywords: Models, Molecular; Protein Conformation, alpha-Helical; 0301 basic medicine; Oncogene Proteins, Fusion; Protein Conformation; Science; Gene Expression; Mitosis; Protein Serine-Threonine Kinases; Crystallography, X-Ray; Article; Cell Line; 03 medical and health sciences; Models; Cell Line, Tumor; Chromosome Segregation; Humans; Protein Interaction Domains and Motifs; Fusion; Centrioles; Oncogene Proteins; Tumor; Crystallography; Binding Sites; Osteoblasts; alpha-Helical; Q; Intracellular Signaling Peptides and Proteins; Molecular; Protein-Serine-Threonine Kinases; Recombinant Proteins; Cytoskeletal Proteins; Mutation; X-Ray; beta-Strand; Protein Conformation, beta-Strand; Protein Binding

AbstractCentrosomes are required for faithful chromosome segregation during mitosis. They are composed of a centriole pair that recruits and organizes the microtubule-nucleating pericentriolar material. Centriole duplication is tightly controlled in vivo and aberrations in this process are associated with several human diseases, including cancer and microcephaly. Although factors essential for centriole assembly, such as STIL and PLK4, have been identified, the underlying molecular mechanisms that drive this process are incompletely understood. Combining protein proximity mapping with high-resolution structural methods, we identify CEP85 as a centriole duplication factor that directly interacts with STIL through a highly conserved interaction interface involving a previously uncharacterised domain of STIL. Structure-guided mutational analyses in vivo demonstrate that this interaction is essential for efficient centriolar targeting of STIL, PLK4 activation and faithful daughter centriole assembly. Taken together, our results illuminate a molecular mechanism underpinning the spatiotemporal regulation of the early stages of centriole duplication.