Adaptable centriole biogenesis via the intrinsically disordered protein ALMS1

Area of Science:

• Cell Biology
• Structural Biology
• Biophysics

Background:

• Centriole biogenesis is a complex process traditionally viewed as template-free.
• The precise mechanisms governing the dynamic assembly and disassembly of the cartwheel scaffold remain largely unknown.
• Understanding centriole duplication is crucial for cell cycle regulation and understanding developmental disorders.

Purpose of the Study:

• To elucidate the role of intrinsically disordered proteins (IDPs) in centriole biogenesis.
• To identify novel cofactors involved in cartwheel scaffold formation and dynamics.
• To investigate the impact of mutations in key regulatory proteins on centriole architecture.

Main Methods:

• Identification of ALMS1 as a key cofactor in cartwheel seed formation.
• Characterization of cartwheel seed (CS) assembly using CEP152/CEP63 complexes.
• Analysis of ALMS1's role in CS disassembly during mitosis.
• Investigation of ALMS1 hypomorph mutations and ALMS1 depletion effects on centriole biogenesis.

Main Results:

• ALMS1 acts as an external cofactor, inducing cartwheel seed formation without direct incorporation.
• Cartwheel seeds form as nanoscale rings of CEP152/CEP63 complexes during interphase.
• ALMS1 is involved in cartwheel seed disassembly upon mitotic entry.
• ALMS1 mutations lead to aberrant centriole amplification and ectopic centriole formation.
• ALMS1 depletion prevents cartwheel seed assembly, while its reintroduction initiates de novo biogenesis.

Conclusions:

• Centriole biogenesis is regulated by adaptable, extrinsic transformation cues mediated by IDPs like ALMS1.
• IDP-mediated cartwheel seed assembly-disassembly cycles are crucial for regulating centriole architecture.
• The findings suggest a mechanism for generating diverse, heritable centriole architectures through selection, challenging the notion of a single canonical form.