NSF & SNAP

Background of NSF and SNAPs

Neural functions and physiological activities are finely controlled by neural signals. In the central nervous system, signals, or neural impulses, are transmitted in the form of electrical signals of action potentials on the axons of neurons, while through neurotransmitters between neurons. When the neural impulses reach the axon terminals or synaptosomes, the synaptic vesicles containing neurotransmitters fuse with the presynaptic membrane and release the neurotransmitters into the synaptic cleft through exocytosis. The released neurotransmitters bind to the receptors on the postsynaptic membrane, resulting in the excitation of postsynaptic neurons.

Therefore, the release of neurotransmitters via exocytosis is an essential and critical process of neuronal information transmission. This neurotransmitter transmission is strictly regulated by a series of proteins, of which N-ethylmaleimide sensitive fusion proteins (NSF) and Soluble NSF attachment proteins (SNAPs) are two important proteins involved in membrane fusion.

What are NSF and SNAPs?

NSF is a member of the AAA family of ATPases encoded by the human NSF gene. It is a homohexameric protein with a featured barrel-like structure containing a central cavity. Each subunit of NSF hexamer consists of three domains, D1 and D2 domains at the C-terminus and an N-terminal domain containing 2 subdomains. In NSF, the D1 domain is responsible for ATPase activity. Although the D2 domain is homologous to the D1 domain, it has little relationship with the catalytic activity, which is a key part of the homohexameric structure. The N-terminal domain mediates binding to the SNAP.

SNAPs are a group of adaptor proteins attaching NSF to membranes, and also play an important role in the intra-Golgi transportation function. In humans, three SNAP isoforms have been isolated and identified from the brain, α-SNAP, β-SNAP, and γ-SNAP, all of which are monomeric soluble proteins. α-SNAP is highly homologous with β-SNAP, with 83% identical amino acid sequence. α-SNAP and γ-SNAP are extensively expressed and synergistic in attachment NSF to the membrane, whereas β-SNAP is limitedly expressed in the central nervous system.

Functional Mechanism of NSF and SNAPs in Exocytosis

Both NSF and SNAPs are key factors in vesicle docking, fusion, and exocytosis of neurotransmitters in a Ca²⁺-dependent manner. The mechanism by which NSF and SNAPs participate in exocytosis is still controversial. When the vesicle successfully docks to the target membrane, the α-helical domains of the SNAP receptors (SNAREs) form a stable four-helix bundle, leading the two membranes into proximity. Once the membrane is fused, SNAPs and NSF are recruited, and NSF unravels SNARE complexes by catalyzing the hydrolysis of ATP, releasing the SNAREs to be recycled for reuse in further rounds of membrane fusion.

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