SAS-6 oligomerization: the key to the centriole?

Centrioles are highly ordered structures that organize two key cellular organelles: the centrosome and the cilium. Defects in both organelles are now firmly linked to a wide variety of human diseases1. Centrioles are composed of nine blade-like microtubule triplets, arranged at the end of nine spokes that radiate from a central hub (Fig. 1a). The central hub and spokes are collectively referred to as the central cartwheel: this structure seems to be an essential and early intermediate in the centriole assembly pathway, and it is widely assumed to be responsible for generating the nine-fold symmetry of centrioles (Fig. 1b)2,3. Although proteomic studies indicate that centrioles consist of many proteins4,5, centriole replication seems to depend on a small ‘core’ of proteins (reviewed in refs. 1, 6 and 7). These proteins were first identified in a series of genetic and RNA interference screens in Caenorhabditis elegans; they showed that SPD-2 recruits the kinase ZYG-1 to the mother centriole, which, in turn, recruits a complex of SAS6 and SAS-5 to form a central tube (a structural variant of the central cartwheel that lacks detectable spokes). This complex recruits SAS-4, which is required for the addition of microtubules around the central tube. The central role of SPD-2 in centriole duplication in other species remains controversial8–11, but a functional equivalent of ZYG-1 (the Polo-like kinase Plk4, also known as Sak) and clear functional orthologs of SAS-4, SAS-5 and SAS-6 have been identified, and they have been shown to be intimately involved in centriole duplication in other species. Though Plk-4 is likely to be the crucial initiator of centriole duplication, accumulating evidence suggests that SAS-6 is a key structural component in the early assembly pathway. SAS-6 homologs in Chlamydomonas reinhardtii (Bld-12) and Tetrahymena thermophila (Sas6a) localize to the central cartwheel; Bld12 mutants lack detectable cartwheels and show defects in the nine-fold symmetry of centrioles3,5. Moreover, Drosophila SAS-6 can selfassemble into oligomers in vitro12, and, when overexpressed in embryos, it forms large, irregular tube-like structures that can recruit other centriolar and centrosomal proteins13,14. Intriguingly, when Drosophila SAS-6 is overexpressed together with Ana2 (the Drosophila functional ortholog of SAS-5), the two proteins can assemble into well-ordered tubules that bear a striking resemblance to the cartwheel15. Now, in two landmark papers, the crystal structures of SAS-6 from various species have been solved16,17 (Table 1). These structures provide clues as to how the SAS-6 protein may be organized into a central-cartwheel structure to dictate the nine-fold symmetry of the centriole.