Abstract
Primary microcephaly (MCPH) associated proteins CDK5RAP2, CEP152, WDR62 and CEP63 colocalize at the centrosome. We found that they interact to promote centriole duplication and form a hierarchy in which each is required to localize another to the centrosome, with CDK5RAP2 at the apex, and CEP152, WDR62 and CEP63 at sequentially lower positions. MCPH proteins interact with distinct centriolar satellite proteins; CDK5RAP2 interacts with SPAG5 and CEP72, CEP152 with CEP131, WDR62 with MOONRAKER, and CEP63 with CEP90 and CCDC14. These satellite proteins localize their cognate MCPH interactors to centrosomes and also promote centriole duplication. Consistent with a role for satellites in microcephaly, homozygous mutations in one satellite gene, CEP90, may cause MCPH. The satellite proteins, with the exception of CCDC14, and MCPH proteins promote centriole duplication by recruiting CDK2 to the centrosome. Thus, centriolar satellites build a MCPH complex critical for human neurodevelopment that promotes CDK2 centrosomal localization and centriole duplication.
Highlights
At the heart of the centrosome, the principle microtubule-organizing center of a mammalian cell, are two centrioles
Because CEP72 and SPAG5 are required for the centrosomal localization of CDK5RAP2, and CDK5RAP2 is required for the centrosomal localization of other MCPH-associated proteins CEP152, WDR62 and CEP63, we examined whether the loss of SPAG5 or CEP72 altered the localization of the CDK5RAP2-dependent MCPH proteins
We found that the MCPH-associated proteins CDK5RAP2, CEP152, WDR62 and CEP63 interact with each other and function together to promote centriole duplication
Summary
At the heart of the centrosome, the principle microtubule-organizing center of a mammalian cell, are two centrioles. A pair of centrioles are surrounded by pericentriolar material and centriolar satellites, 70–100 nm diameter electron dense structures that participate in microtubule-based transport (Kubo et al, 1999; Dammermann and Merdes, 2002; Kodani et al, 2010). Centriolar satellites contain PCM1, thought to function in the delivery of proteins to the centrosome (Kim et al, 2008; Kodani et al, 2010). Consistent with this hypothesis, depletion of PCM1 reduces the centrosomal localization of select proteins
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