SNARE protein
Evidence suggests that t-SNAREs form stable subcomplexes which serve as guides for v-SNARE, incorporated into the membrane of a protein-coated vesicle, binding to complete the formation of the SNARE complex.
R-SNAREs are proteins that contribute an arginine (R) residue in the formation of the zero ionic layer in the assembled core SNARE complex.
Q-SNAREs are proteins that contribute a glutamine (Q) residue in the formation of the zero ionic layer in the assembled core SNARE complex.
The targeting of SNAREs is accomplished by altering either the composition of the C-terminal flanking amino acid residues or the length of the transmembrane domain.
[9] The plasma membrane-resident SNAREs have been shown to be present in distinct microdomains or clusters, the integrity of which is essential for the exocytotic competence of the cell.
Then, the hexameric ATPase (of the AAA type) called NSF catalyzes the ATP-dependent unfolding of the SNARE proteins and releases them into the cytosol for recycling.
SNAREs are thought to be the core required components of the fusion machinery and can function independently of additional cytosolic accessory proteins.
Exposure of the zero ionic layer to the water solvent by breaking the flanking leucine zipper leads to instability of the SNARE complex and is the putative mechanism by which
The SM protein Munc18 is thought to play a role in assembly of the SNARE complex, although the exact mechanism by which it acts is still under debate.
In accordance with the "zipper" hypothesis, as the SNARE complex forms, the tightening helix bundle puts torsional force on the transmembrane (TM) domains of synaptobrevin and syntaxin.
The continuum explanation of stalk formation suggests that membrane fusion begins with an infinitesimal radius until it radially expands into a stalk-like structure.
In this molecular view, the splayed-lipid intermediate state is the rate determining barrier rather than the formation of the stalk, which now becomes the free energy minimum.
The ATP hydrolysis-coupled dissociation of SNARE complexes is an energy investment that can be compared to "cocking the gun" so that, once vesicle fusion is triggered, the process takes place spontaneously and at optimum velocity.
A comparable process takes place in muscles, in which the myosin heads must first hydrolyze ATP in order to adapt the necessary conformation for interaction with actin and the subsequent power stroke to occur.
[24] The α-helical domains combine with those of both syntaxin and synaptobrevin (also known as vesicle associated membrane protein or VAMP) to form the 4-α-helix coiled-coil SNARE complex critical to efficient exocytosis.
Syntaxin knockdown studies however, failed to show a decrease in membrane bound SNAP-25 suggesting alternate docking means exist.
[25] The covalent bonding of fatty acid chains to SNAP-25 via thioester linkages with one or more cysteine residues therefore, provides for regulation of docking and ultimately SNARE mediated exocytosis.
[26] The cysteine rich domain of SNAP-25 has also been shown to weakly associate with the plasma membrane possibly allowing it to be localized near the enzyme for subsequent palmitoylation.
The availability of SNAP-25 in the SNARE complex is also theorized to possibly be spatially regulated via localization of lipid microdomains in the target membrane.
[38] The light chain of BoNT acts as a metalloprotease on SNARE proteins that is dependent on Zn(II) ions,[39] cleaving them and eliminating their function in exocytosis.
In each of these cases, Botulinum Neurotoxin causes functional damage to SNARE proteins, which has significant physiological and medical implications.
The light chain has zinc-dependent endopeptidase or more specifically matrix metalloproteinase (MMP) activity through which cleaveage of synaptobrevin or VAMP is carried out.
[42] Cleavage of synaptobrevin affects the stability of the SNARE core by restricting it from entering the low energy conformation which is the target for NSF binding.
During neurosecretion/exocytosis, SNAREs play a crucial role in vesicle docking, priming, fusion, and synchronization of neurotransmitter release into the synaptic cleft.
The span of presynaptic membrane containing the primed vesicles and dense collection of SNARE proteins is referred to as the active zone.
The influx of calcium is sensed by synaptotagmin 1, which in turn dislodges complexin protein and allows the vesicle to fuse with the presynaptic membrane to release neurotransmitter.
[47] Macroautophagy is a catabolic process involving the formation of double-membrane bound organelles called autophagosomes, which aid in degradation of cellular components through fusion with lysosomes.
During autophagy, portions of the cytoplasm are engulfed by a cup-shaped double-membrane structure called a phagophore and eventually become the contents of the fully assembled autophagosome.
Autophagosome biogenesis requires the initiation and growth of phagophores, a process that was once thought to occur through de novo addition of lipids.
[6] SNAREs also occur in plants, where they are essential for vesicle transport to and from ER, Golgi, trans-Golgi network/early endosome, plasma membrane and vacuole.
