A BLOC-1–AP-3 super-complex sorts a cis-SNARE complex into endosome-derived tubular transport carriers

Abstract

Membrane transport carriers fuse with target membranes through engagement of cognate vSNAREs and tSNAREs on each membrane. How vSNAREs are sorted into transport carriers is incompletely understood. Here we show that VAMP7, the vSNARE for fusing endosome-derived tubular transport carriers with maturing melanosomes in melanocytes, is sorted into transport carriers in complex with the tSNARE component STX13. Sorting requires either recognition of VAMP7 by the AP-3δ subunit of AP-3 or of STX13 by the pallidin subunit of BLOC-1, but not both. Consequently, melanocytes expressing both AP-3δ and pallidin variants that cannot bind their respective SNARE proteins are hypopigmented and fail to sort BLOC-1–dependent cargo, STX13, or VAMP7 into transport carriers. However, SNARE binding does not influence BLOC-1 function in generating tubular transport carriers. These data reveal a novel mechanism of vSNARE sorting by recognition of redundant sorting determinants on a SNARE complex by an AP-3–BLOC-1 super-complex.

SNARE proteins: zip codes in vesicle targeting?

“…Similarly, the N-terminal domain of the SNARE vti1b binds to the clathrin adaptor EpsinR [ 90–92 ]. More complex mechanisms involving multiple factors have also emerged, which determine the intracellular localization of a given SNARE or mediate sorting of two SNAREs together [ 93 , 94 ].…”

New insights into the pathogenesis of Hermansky–Pudlak syndrome

“…Further tubule elongation is cooperated with Annexin A2 or WASH complex to nucleate Arp2/3‐dependent actin filaments (Delevoye et al, 2016; Ryder et al, 2013). The BLOC‐1 sorting pathway requires syntaxin‐13‐ mediated by the BLOC‐1/AP‐3 super complex (Bowman et al, 2021). Furthermore, BLOC‐2 may tether this recycling tubule structures to melanosomes (Dennis et al, 2015).…”

Robustness and innovation along the endocytic route: Lessons from darkness

“…Selective cargo loading is accomplished by cytoplasmic protein complexes that sort these complexes into a nascent carrier ( 1 ). In this issue, Bowman et al ( 2 ) focused on two sorting complexes, the adaptor complex adaptor protein-3 (AP-3) and biogenesis of lysosome-related organelles complex (BLOC)-1 complex ( 3 ). Once formed, membrane-bound carriers must fuse with their target organelle to deliver their content ( 1 ).…”

“…Preventing an R-SNARE from loading into its carrier impairs carrier fusion with the target membrane and results in dramatic consequences for cells and organisms. For example, removal of the R-SNARE from carriers bound to melanosomes generates melanosomes that fail to produce pigment, a cellular phenotype used by Bowman et al ( 2 ). In the case of synaptic vesicles, elimination of R-SNAREs from these vesicles prevents their fusion with the plasmalemma halting neurotransmission with overt manifestations such as paralysis ( 4 ).…”

“…This represents a robustness built by copies of the same type of entities, much like the two-parachute fail-safe approach in skydiving. In contrast, Bowman et al present the first example where the system’s resilience is built by two dissimilar strategies acting on the same R-SNARE ( 2 ). This would be analogous to replacing one of the two parachutes with a jet pack during skydiving.…”