Publication

Article Metrics

Citations


Online attention

Disease-associated mutations in CEP120 destabilize the protein and impair ciliogenesis

DOI: 10.1016/j.celrep.2018.04.100 DOI Help

Authors: Nimesh Joseph (Cancer Research UK Cambridge Institute, University of Cambridge) , Caezar Al-Jassar (Medical Research Council Laboratory of Molecular Biology) , Christopher M. Johnson (Medical Research Council Laboratory of Molecular Biology) , Antonina Andreeva (Medical Research Council Laboratory of Molecular Biology) , Deepak D. Barnabas (Medical Research Council Laboratory of Molecular Biology) , Stefan M. V. Freund (Medical Research Council Laboratory of Molecular Biology) , Fanni Gergely (Cancer Research UK Cambridge Institute, University of Cambridge) , Mark Van Breugel (Medical Research Council Laboratory of Molecular Biology)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Cell Reports , VOL 23 , PAGES 2805 - 2818

State: Published (Approved)
Published: May 2018
Diamond Proposal Number(s): 8547 , 11235

Open Access Open Access

Abstract: Ciliopathies are a group of genetic disorders caused by a failure to form functional cilia. Due to a lack of structural information, it is currently poorly understood how ciliopathic mutations affect protein functionality to give rise to the underlying disease. Using X-ray crystallography, we show that the ciliopathy-associated centriolar protein CEP120 contains three C2 domains. The point mutations V194A and A199P, which cause Joubert syndrome (JS) and Jeune asphyxiating thoracic dystrophy (JATD), respectively, both reduce the thermostability of the second C2 domain by targeting residues that point toward its hydrophobic core. Genome-engineered cells homozygous for these mutations have largely normal centriole numbers but show reduced CEP120 levels, compromised recruitment of distal centriole markers, and deficient cilia formation. Our results provide insight into the disease mechanism of two ciliopathic mutations in CEP120, identify putative binding partners of CEP120 C2B, and suggest a complex genotype-phenotype relation of the CEP120 ciliopathy alleles.

Journal Keywords: centriole; centrosome; basal body; cilia; ciliopathy; CEP120; Joubert syndrome; JATD; Jeuene syndrome

Diamond Keywords: Joubert Syndrome; Jeune Asphyxiating Thoracic Dystrophy (JATD)

Subject Areas: Biology and Bio-materials


Instruments: I02-Macromolecular Crystallography , I03-Macromolecular Crystallography , I04-Macromolecular Crystallography

Other Facilities: ESRF

Added On: 05/06/2018 15:30

Documents:
1-s2.0-S2211124718306788-main.pdf

Discipline Tags:

Life Sciences & Biotech Genetics Health & Wellbeing Non-Communicable Diseases Structural biology

Technical Tags:

Diffraction Macromolecular Crystallography (MX)