Sandbox Reserved 823: Difference between revisions
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== '''Membrane fusion mechanism''' == | == '''Membrane fusion mechanism''' == | ||
[[Image:Membrane_fusion.jpg|thumbnail||800 px||center| '''Membrane fusion mechanism | [[Image:Membrane_fusion.jpg|thumbnail||800 px||center| '''Membrane fusion mechanism''']] | ||
Membrane Fusion requires the '''assembly of the core complex'''. '''Free t-SNAREs''' that are organized in '''clusters''' first assemble into acceptor complexes thanks to '''SM''' (Sec1/Munc18-related) '''proteins'''. Acceptor complexes can then interact with the '''v-SNAREs''' through the N-terminal domain of the SNARE motif. This enables the formation of '''four-helical trans-complexes''', in which only the N-terminal portions of the SNARE motifs are bound. This binding evolves from a '''loose''' to a '''tight state''', thus leading to the formation of a '''fusion pore'''. During the fusion, the conformation relaxes to a '''cis-configuration'''. Cis-complexes dissociate thanks to '''proteins''' and '''cofactors (SNAPs)'''. T- and v-SNAREs can be separated and recycled.<ref> PMID: 16912714 </ref> | Membrane Fusion requires the '''assembly of the core complex'''. '''Free t-SNAREs''' that are organized in '''clusters''' first assemble into acceptor complexes thanks to '''SM''' (Sec1/Munc18-related) '''proteins'''. Acceptor complexes can then interact with the '''v-SNAREs''' through the N-terminal domain of the SNARE motif. This enables the formation of '''four-helical trans-complexes''', in which only the N-terminal portions of the SNARE motifs are bound. This binding evolves from a '''loose''' to a '''tight state''', thus leading to the formation of a '''fusion pore'''. During the fusion, the conformation relaxes to a '''cis-configuration'''. Cis-complexes dissociate thanks to '''proteins''' and '''cofactors (SNAPs)'''. T- and v-SNAREs can be separated and recycled.<ref> PMID: 16912714 </ref> | ||
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=== '' “0”- | === '' “0”-layer'' === | ||
[[Image:Layers.png|thumbnail||1100 px||left| '''Topology of the 16 layers of the SNARE complex | [[Image:Layers.png|thumbnail||1100 px||left| '''Topology of the 16 layers of the SNARE complex''']] | ||
The centre of the four-helix bundle is constituted of '''16 layers'''. These layers are composed of '''hydrophobic side chains''', which are perpendicular to the axis of the four-helix bundle, except for the central '''“0”-layer'''. This last one consists of '''three glutamine (Q)''' and '''one arginine (R)''' highly conserved residues. Those highly conserved residues have led to a new classification of SNAREs into '''Q- and R-SNAREs'''. <ref> PMID: 9861047 </ref> Almost all membrane fusion reactions require one R-SNARE and three Q-SNAREs:Qa, Qb and Qc.<ref> PMID: 11237004 </ref><ref> PMID: 11001046 </ref> In many cases, the R-SNARE is in the vesicle, and the three Q-SNAREs are in the target membrane. For the early endosomal SNARE complex, syntaxin 13, vti1a, syntaxin 6, and VAMP4 were respectively classified as Qa-, Qb-, Qc- and R-SNAREs. | The centre of the four-helix bundle is constituted of '''16 layers'''. These layers are composed of '''hydrophobic side chains''', which are perpendicular to the axis of the four-helix bundle, except for the central '''“0”-layer'''. This last one consists of '''three glutamine (Q)''' and '''one arginine (R)''' highly conserved residues. Those highly conserved residues have led to a new classification of SNAREs into '''Q- and R-SNAREs'''. <ref> PMID: 9861047 </ref> Almost all membrane fusion reactions require one R-SNARE and three Q-SNAREs: Qa, Qb and Qc.<ref> PMID: 11237004 </ref><ref> PMID: 11001046 </ref> In many cases, the R-SNARE is in the vesicle, and the three Q-SNAREs are in the target membrane. For the early endosomal SNARE complex, syntaxin 13, vti1a, syntaxin 6, and VAMP4 were respectively classified as Qa-, Qb-, Qc- and R-SNAREs. | ||
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== '''Regulation''' == | == '''Regulation''' == | ||
In addition to SNARE motifs and membrane anchors, SNARE proteins have '''autonomously folding N-terminal domains'''. These autonomously folded domains are able to '''regulate SNARE assembly'''. For example, synthaxin 7 has a '''three-helix-bundle domain''', which with the profiling-like domain Ykt6p of yeast can lightly '''inhibit the SNARE assembly'''.<ref> PMID: 11474112 </ref> Sso1p is the yeast ortholog of syntax in. Ssop has also '''three-helix-bundle domain''' that can bind to the SNARE motif. This binding generates a closed conformation that strongly '''inhibits the entry of Sso1p''' into SNARE complexes.<ref> PMID: 10048921 </ref><ref> PMID: 11017200 </ref><ref> PMID: 11777922 </ref><ref> PMID: 9731774 </ref> The main role of these autonomously folded domains is still under research. However, one of the known functions is the '''recruitment''' of other trafficking proteins thanks to the open/closed equilibrium of some SNAREs. | In addition to SNARE motifs and membrane anchors, SNARE proteins have '''autonomously folding N-terminal domains'''. These autonomously folded domains are able to '''regulate SNARE assembly'''. For example, synthaxin 7 has a '''three-helix-bundle domain''', which with the profiling-like domain Ykt6p of yeast can lightly '''inhibit the SNARE assembly'''.<ref> PMID: 11474112 </ref> Sso1p is the yeast ortholog of syntax in. Ssop has also a '''three-helix-bundle domain''' that can bind to the SNARE motif. This binding generates a closed conformation that strongly '''inhibits the entry of Sso1p''' into SNARE complexes.<ref> PMID: 10048921 </ref><ref> PMID: 11017200 </ref><ref> PMID: 11777922 </ref><ref> PMID: 9731774 </ref> The main role of these autonomously folded domains is still under research. However, one of the known functions is the '''recruitment''' of other trafficking proteins thanks to the open/closed equilibrium of some SNAREs. | ||
== ''' SNAREs and pulmonary hypertension ''' == | == ''' SNAREs and pulmonary hypertension ''' == | ||
'''Pulmonary hypertension''' (PH) corresponds to an '''increase of blood pressure''' in the pulmonary artery, pulmonary vein, or pulmonary capillaries leading to shortness of breath, dizziness, fainting, leg swelling and other symptoms. Pulmonary hypertension can be a '''severe disease''', characterized by a decreased exercise tolerance and heart failure. The origin of the disease seems to be a | '''Pulmonary hypertension''' (PH) corresponds to an '''increase of blood pressure''' in the pulmonary artery, pulmonary vein, or pulmonary capillaries leading to shortness of breath, dizziness, fainting, leg swelling and other symptoms. Pulmonary hypertension can be a '''severe disease''', characterized by a decreased exercise tolerance and heart failure. The origin of the disease seems to be a Golgi-dysfunction. Indeed, dysfunction of Golgi tethers, SNAPs and '''SNAREs''' apparently leads to pulmonary hypertension.<ref> PMID:17416597 </ref> | ||
