SNARE chaperone Sly1 directly mediates close-range vesicle tethering

TY - JOUR

T1 - SNARE chaperone Sly1 directly mediates close-range vesicle tethering

AU - Duan, Mengtong

AU - Plemel, Rachael L.

AU - Takenaka, Tomoka

AU - Lin, Ariel

AU - Delgado, Beatriz Marie

AU - Nattermann, Una

AU - Nickerson, Daniel P.

AU - Mima, Joji

AU - Miller, Elizabeth A.

AU - Merz, Alexey J.

PY - 2024/6/3

Y1 - 2024/6/3

N2 - The essential Golgi protein Sly1 is a member of the Sec1/mammalian Unc-18 (SM) family of SNARE chaperones. Sly1 was originally identified through remarkable gain-of-function alleles that bypass requirements for diverse vesicle tethering factors. Employing genetic analyses and chemically defined reconstitutions of ER–Golgi fusion, we discovered that a loop conserved among Sly1 family members is not only autoinhibitory but also acts as a positive effector. An amphipathic lipid packing sensor (ALPS)-like helix within the loop directly binds high-curvature membranes. Membrane binding is required for relief of Sly1 autoinhibition and also allows Sly1 to directly tether incoming vesicles to the Qa-SNARE on the target organelle. The SLY1-20 mutation bypasses requirements for diverse tethering factors but loses this ability if the tethering activity is impaired. We propose that long-range tethers, including Golgins and multisubunit tethering complexes, hand off vesicles to Sly1, which then tethers at close range to initiate trans-SNARE complex assembly and fusion in the early secretory pathway.

AB - The essential Golgi protein Sly1 is a member of the Sec1/mammalian Unc-18 (SM) family of SNARE chaperones. Sly1 was originally identified through remarkable gain-of-function alleles that bypass requirements for diverse vesicle tethering factors. Employing genetic analyses and chemically defined reconstitutions of ER–Golgi fusion, we discovered that a loop conserved among Sly1 family members is not only autoinhibitory but also acts as a positive effector. An amphipathic lipid packing sensor (ALPS)-like helix within the loop directly binds high-curvature membranes. Membrane binding is required for relief of Sly1 autoinhibition and also allows Sly1 to directly tether incoming vesicles to the Qa-SNARE on the target organelle. The SLY1-20 mutation bypasses requirements for diverse tethering factors but loses this ability if the tethering activity is impaired. We propose that long-range tethers, including Golgins and multisubunit tethering complexes, hand off vesicles to Sly1, which then tethers at close range to initiate trans-SNARE complex assembly and fusion in the early secretory pathway.

KW - Biochemistry

KW - Genetics

KW - Organelles

KW - Trafficking

U2 - 10.1083/jcb.202001032

DO - 10.1083/jcb.202001032

M3 - Article

C2 - 38478018

SN - 0021-9525

VL - 223

JO - Journal of Cell Biology

JF - Journal of Cell Biology

IS - 6

M1 - e202001032

ER -