Structural basis and pathological implications of the dimeric OS9-SEL1L-HRD1 ERAD Core Complex

Area of Science:

• Molecular Biology
• Structural Biology
• Cellular Quality Control

Background:

• The SEL1L-HRD1 complex is a key component of endoplasmic reticulum-associated degradation (ERAD), essential for clearing misfolded proteins.
• The precise molecular architecture and disease mechanisms of mammalian ERAD have been poorly understood.

Purpose of the Study:

• To determine the cryo-electron microscopy (cryo-EM) structure of the core mammalian ERAD complex.
• To elucidate the pathogenic mechanisms underlying ERAD dysfunction and its link to human diseases.

Main Methods:

• Cryo-electron microscopy (cryo-EM) to determine the structure of the OS9-SEL1L-HRD1 complex.
• Mutagenesis and crosslinking assays to validate structural findings and assess functional impact.

Main Results:

• The cryo-EM structure reveals a dimeric SEL1L-HRD1 complex with a claw-like OS9-SEL1L structure in the ER lumen and a membrane-bound HRD1 dimer.
• Pathogenic mutations in SEL1L and HRD1 were identified at critical interfaces, disrupting complex formation, ERAD activity, and substrate processing.
• Structural insights explain how destabilization of the ERAD machinery contributes to human disease.

Conclusions:

• The study provides the first structural and functional insights into the mammalian SEL1L-HRD1 ERAD machinery.
• Understanding the structural basis of ERAD dysfunction is crucial for elucidating disease mechanisms and potential therapeutic strategies.