Syntaxin 1A transmembrane domain palmitoylation induces a fusogenic conformation

Area of Science:

• Biochemistry
• Molecular Biology
• Neuroscience

Background:

• Neurotransmitter release relies on synaptic vesicle fusion, mediated by SNARE proteins.
• Syntaxin 1A (Stx1A) palmitoylation at C271/C272 is linked to spontaneous neurotransmitter release.
• The role of SNARE transmembrane domain (TMD) palmitoylation in membrane fusion is not fully understood.

Purpose of the Study:

• To investigate the structural and functional impact of SNARE TMD palmitoylation on membrane fusion.
• To elucidate the mechanism by which Stx1A palmitoylation influences neurotransmitter release.

Main Methods:

• Coarse-grained molecular-dynamics simulations using the MARTINI force field.
• Simulations of individual SNARE proteins, t-SNARE complexes, and fusion pore formation.

Main Results:

• Stx1A palmitoylation stabilizes an upright SNARE domain conformation, facilitating early SNARE complex formation.
• Stx1A TMD palmitoylation delays fusion pore opening and reduces flicker-open times.
• Synaptobrevin 2 (Syb2) palmitoylation did not significantly impact fusion pore dynamics.

Conclusions:

• Stx1A TMD palmitoylation plays a dual role, promoting early SNARE complex formation and influencing later fusion pore dynamics.
• SNARE TMD palmitoylation is crucial for multiple stages of neurotransmitter release.
• These findings provide mechanistic insights into SNARE-mediated membrane fusion.