Adaptable centriole biogenesis via the intrinsically disordered protein ALMS1

Abstract

Biogenesis of subcellular structures like centrioles is viewed as a physical transformation wherein elementary constituents form order without preexisting templates. Centrioles grow with precision from a composite scaffold known as the cartwheel, which is thought to self-assemble without templates and disassemble following centriole growth; however, the mechanism governing cartwheel assembly-disassembly dynamics remains obscure. Here, we identify ALMS1, a disease-linked, intrinsically disordered protein (IDP), as an external mediator of cartwheel dynamics that causes a seed for cartwheel--and thus centriole--formation without itself incorporating into the seed structure. The cartwheel seed (CS), characterized as a dense composite of CEP152/CEP63 protein complexes, forms in interphase and adopts a nanoscale, concentric ring from which the cartwheel grows. Upon mitotic entry, CSs recruit ALMS1 while disassembling into constituents associating with ALMS1 in proximity, correlating with cartwheel assembly-disassembly cycles. Hypomorph, disease-linked ALMS1 mutations trigger cartwheel expansion and shedding by its own grown procentriole, in turn forming ectopic centrioles, leading to perpetual reciprocal amplification. Without ALMS1, CS formation fails, negating centriole biogenesis, whereas reintroducing ALMS1 initializes biogenesis anew, creating diverse yet heritable architectures that evolve through selection, instead of generating a single canonical form. These results suggest that centriole biogenesis is grounded on adaptable transformation cues extrinsic to its constituents, propagating via IDP-mediated CS assembly-disassembly cycles, a process we conjecture involves memory.