The human GID complex engages two independent modules for substrate recruitment

Area of Science:

• Biochemistry
• Molecular Biology
• Structural Biology

Background:

• The human GID (hGID) complex is a crucial E3 ubiquitin ligase involved in glucose metabolism and cell cycle.
• Its precise biochemical functions and substrate recognition mechanisms remain largely unelucidated.

Purpose of the Study:

• To elucidate the biochemical function and substrate recruitment mechanisms of the multi-subunit hGID complex.
• To investigate the roles of WDR26 and GID4 in substrate recognition and complex regulation.

Main Methods:

• Biochemical assays
• Cross-linking mass spectrometry
• Cryo-electron microscopy (Cryo-EM)

Main Results:

• hGID utilizes two distinct modules, WDR26 and GID4, for substrate recruitment.
• WDR26/RanBP9 targets HBP1, while GID4 targets ZMYND19, independent of a Pro/N-end degron.
• ARMC8α regulates GID4 binding and ligase activity; ARMC8β forms a stable complex that excludes GID4.
• Cryo-EM revealed WDR26 within a tetrameric architecture and suggested distinct binding sites for GID4 and WDR26/Gid7.

Conclusions:

• The hGID complex employs modular substrate recruitment strategies.
• Understanding hGID's mechanisms provides insights into E3 ligase regulation and substrate specificity.