Matthew L Starr, Robert P Sparks, Andres S Arango, Logan R Hurst, Zhiyu Zhao,
Muyun Lihan, Jermaine L Jenkins, Emad Tajkhorshid, and Rutilio A Fratti.
Phosphatidic acid induces conformational changes in Sec18 protomers
that prevent SNARE priming.
Journal of Biological Chemistry, 294:3100-3116, 2019.
(PMC: PMC6398130)
STAR2019-ET
Eukaryotic cell homeostasis requires transfer of cellular components among
organelles and relies on membrane fusion catalyzed by SNARE proteins.
Inactive SNARE bundles are reactivated by hexameric N-ethylmaleimide–
sensitive factor, vesicle-fusing ATPase (Sec18/NSF)-driven disassembly that
enables a new round of membrane fusion. We previously found that
phosphatidic acid (PA) binds Sec18 and thereby sequesters it from SNAREs
and that PA dephosphorylation dissociates Sec18 from the membrane,
allowing it to engage SNARE complexes. We now report that PA also induces
conformational changes in Sec18 protomers and that hexameric Sec18
cannot bind PA membranes. Molecular dynamics (MD) analyses revealed
that the D1 and D2 domains of Sec18 contain PA-binding sites and that the
residues needed for PA binding are masked in hexameric Sec18. Importantly,
these simulations also disclosed that a major conformational change occurs
in the linker region between the D1 and D2 domains, which is distinct from
the conformational changes that occur in hexameric Sec18 during SNARE
priming. Together, these findings indicate that PA regulates Sec18 function
by altering its architecture and stabilizing membrane-bound Sec18
protomers.
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