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Mutations in SKI in Shprintzen–Goldberg syndrome lead to attenuated TGF-β responses through SKI stabilization

DOI: 10.7554/eLife.63545 DOI Help

Authors: Ilaria Gori (The Francis Crick Institute) , Roger George (The Francis Crick Institute) , Andrew G. Purkiss (The Francis Crick Institute) , Stephanie Strohbuecker (The Francis Crick Institute) , Rebecca A Randall (The Francis Crick Institute) , Roksana Ogrodowicz (The Francis Crick Institute) , Virginie Carmignac (The Francis Crick Institute) , Laurence Faivre (INSERM - Université de Bourgogne UMR1231 GAD) , Dhira Joshi (The Francis Crick Institute) , Svend Kjær (The Francis Crick Institute) , Caroline S Hill (The Francis Crick Institute)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Elife , VOL 10

State: Published (Approved)
Published: January 2021
Diamond Proposal Number(s): 13775

Open Access Open Access

Abstract: Shprintzen–Goldberg syndrome (SGS) is a multisystemic connective tissue disorder, with considerable clinical overlap with Marfan and Loeys–Dietz syndromes. These syndromes have commonly been associated with enhanced TGF-β signaling. In SGS patients, heterozygous point mutations have been mapped to the transcriptional co-repressor SKI, which is a negative regulator of TGF-β signaling that is rapidly degraded upon ligand stimulation. The molecular consequences of these mutations, however, are not understood. Here we use a combination of structural biology, genome editing, and biochemistry to show that SGS mutations in SKI abolish its binding to phosphorylated SMAD2 and SMAD3. This results in stabilization of SKI and consequently attenuation of TGF-β responses, both in knockin cells expressing an SGS mutation and in fibroblasts from SGS patients. Thus, we reveal that SGS is associated with an attenuation of TGF-β-induced transcriptional responses, and not enhancement, which has important implications for other Marfan-related syndromes.

Diamond Keywords: Shprintzen-Goldberg Syndrome (SGS)

Subject Areas: Biology and Bio-materials

Instruments: I24-Microfocus Macromolecular Crystallography

Added On: 03/02/2021 13:36


Discipline Tags:

Life Sciences & Biotech Genetics Health & Wellbeing Structural biology Chemistry Biochemistry

Technical Tags:

Diffraction Macromolecular Crystallography (MX)