VPS18 recruits VPS41 to the human HOPS complex via a RING-RING interaction

Area of Science:

• Cell biology
• Molecular biology
• Protein complex assembly

Background:

• Eukaryotic membrane fusion relies on conserved tethering complexes like CORVET and HOPS.
• While extensively studied in yeast, metazoan CORVET and HOPS complexes remain less understood.
• Both complexes consist of six subunits, including a shared four-subunit core and two unique subunits, crucial for endomembrane fusion.

Purpose of the Study:

• To investigate the role of C-terminal zinc-finger domains in the assembly of human CORVET and HOPS complexes.
• To elucidate the specific molecular interactions governing subunit recruitment within these essential cellular machinery.

Main Methods:

• Biochemical techniques were employed to analyze protein-protein interactions.
• Studies utilized endogenous complexes within cellular contexts to assess domain contributions.
• Comparative analysis across eukaryotic species highlighted evolutionary divergence in complex assembly.

Main Results:

• Human VPS18 and VPS41 directly interact via their zinc-containing RING domains, forming a stable heterodimer.
• The VPS18 RING domain is essential for recruiting VPS41 to the HOPS core complex.
• Human VPS8, the CORVET analog to VPS41, requires both its RING and a disordered C-terminal domain for integration into CORVET.

Conclusions:

• The zinc-finger domains play critical, yet distinct, roles in the assembly of human HOPS and CORVET complexes.
• VPS18-VPS41 interaction via RING domains is a key step in HOPS assembly, a mechanism not conserved in yeast.
• HOPS and CORVET utilize divergent molecular strategies to incorporate their unique subunits, VPS41 and VPS8, respectively.