The VINE complex is a VPS9-domain GEF-containing SNX-BAR coat involved in endosomal sorting

Abstract

Membrane trafficking pathways perform important roles in establishing and maintaining the endolysosomal network. Retrograde protein sorting from the endosome is promoted by conserved SNX-BAR-containing coat complexes including retromer which enrich cargo at tubular microdomains and generate transport carriers. In metazoans, retromer cooperates with VARP, a conserved VPS9-domain GEF, to direct an endosomal recycling pathway. The function of the yeast VARP homolog Vrl1 has been overlooked due an inactivating mutation in commonly studied strains. Here, we demonstrate that Vrl1 has features of a SNX-BAR coat protein and forms an obligate complex with Vin1, the paralog of the retromer SNX-BAR protein Vps5. Unique features in the Vin1 N-terminus allow Vrl1 to distinguish it from Vps5, thereby forming what we have named the VINE complex. VINE occupies endosomal tubules and promotes the delivery of a conserved mannose 6-phosphate receptor-like protein to the vacuolar membrane. In addition to sorting functions, membrane recruitment by Vin1 is essential for Vrl1 GEF activity, suggesting that VINE is a multifunctional coat complex that regulates trafficking and signaling events at the endosome.

Molecular basis for the assembly of the Vps5-Vps17 SNX-BAR proteins with Retromer

“…8 ). As this work was being prepared, similar findings were reported by Shortill and colleagues, providing further verification of these results 50 .…”

“…Current data suggests that the metazoan SNX1 and SNX2 proteins most likely associate indirectly with Retromer, potentially through SNX27 to form a cargo handover complex 53,54 , although the precise spatial and temporal sequence of events of this are unknown. In addition to SNX1 and SNX2, the yeast SNX-BAR protein Vin1 (also known as YKR078W/Vps501) has been reported to associate with the VARP homolog Vrl1 through its unstructured N-termini to form a novel endosomal transport carrier 60 . Although Vrl1 has a PX-like and a BAR domain, the interaction does not rely on the typical BAR domain dimerization.…”