ALS mutations disrupt self-association between the ubiquilin STI1 hydrophobic groove and internal placeholder sequences - PubMed
5 hours ago
- #Proteostasis
- #Ubiquilins
- #Amyotrophic Lateral Sclerosis
- ALS mutations disrupt the interaction between the ubiquilin STI1 domain and internal placeholder sequences.
- The study presents the first crystal structure of a ubiquilin-family STI1 domain bound to a transmembrane domain (TMD).
- Ubiquilins contain conserved internal sequences that bind to the STI1 domain, including the PXX-repeat region, a hotspot for ALS mutations.
- These placeholder sequences prevent solvent exposure of the STI1 hydrophobic groove and contribute to ubiquilin phase-separation.
- The findings provide insights into the molecular basis of ALS pathogenesis and the role of STI1 domains in ubiquilin chaperone activity and phase separation.