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13  structures 451  species 0  interactions 1768  sequences 16  architectures

Family: Synaphin (PF05835)

Summary: Synaphin protein

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This is the Wikipedia entry entitled "Complexin". More...

Complexin Edit Wikipedia article

Synaphin
PDB 1kil EBI.jpg
3-D structure of the Complexin/SNARE complex
Identifiers
SymbolSynaphin
PfamPF05835
InterProIPR008849
SCOP21l4a / SCOPe / SUPFAM

Complexin (also known as synaphin) refers to a one of a small set of eukaryotic cytoplasmic neuronal proteins which binds to the SNARE protein complex (SNAREpin) with a high affinity. These are called synaphin 1 and 2. In the presence of Ca2+, the transport vesicle protein synaptotagmin displaces complexin, allowing the SNARE protein complex to bind the transport vesicle to the presynaptic membrane.

Complexin acts as both an inhibitor and a facilitator of synaptic vesicle fusion and neurotransmitter release. In one conformation, it clamps SNAREpin complexes, preventing vesicle fusion, while in a different conformation it releases the SNAREpins, allowing synaptotagmin to trigger fusion.[1] Whereas complexin is not necessary for synaptic vesicle exocytosis, it does increase neurotransmitter release by 60–70% as demonstrated by complexin gene knockout in mice.[2] A number of human neurological diseases have been linked to a deficiency of complexin.

Synaphin can promote exocytosis by promoting interaction between the complementary syntaxin and synaptobrevin transmembrane regions that reside in opposing membranes prior to fusion.[2]

Structure and Binding

Complexin is a small highly charged cytosolic protein that is hydrophilic, rich in glutamic acid and lysine residues.[3] Complexin's central region (amino acids 48–70) binds to the SNARE core as an anti-parallel α-helix, which attaches complexin to the SNARE complex. It interacts selectively with the ternary SNARE complex but not with monomeric SNARE proteins. Complexin binds to the groove between the synaptobrevin and syntaxin helices. Complexin stabilizes the C-terminal part of the SNARE complex.

Function

Complexin acts as a positive regulator of synaptic vesicle exocytosis, and binds selectively to the neuronal SNARE complex. Complexin has a two-fold function in that it can act as either a promoter or an inhibitor of vesicle fusion. This dual-functionality is dependent upon synaptic activity such as a depolarizing stimulus arriving at the synapse. By acting as a fusion clamp in inhibiting fusion, and a promoter during depolarization, complexin concentration levels regulate vesicle pool size such as that of the ready releasable pool, important for short term response changes.[4]

Complexin Acts to Inhibit Fusion - Fusion Clamping

Inhibition of fusion is necessary to prevent spontaneous exocytosis of vesicles into the synapse. If a clamp does not hold synaptic vesicle pools stable and inhibit them from fusing, the potential for spontaneous firing and depletion of the vesicle pool is much greater. It is believed that the C-terminal domain of complexin is responsible for this inhibitory function.[5] In several eukaryotic organisms, mutations to complexin were linked to dramatic increases in spontaneous exocytosis rates.[6]

A possible mechanism for how complexin mechanistically anchors vesicles to prevent fusion involves inhibitory binding to the assembling SNARE complex.[7] It is suggested that complexin's N-terminal alpha-helix domain incorporates itself into the SNARE complex helix bundle and prevents zippering of the assembly.[4][8] In contrast to this, another hypothesis is that complexin, independent of synaptotagmin interactions, cross-links with SNARE complexes in a zig-zag array.[7] Recent data supports the former, that synaptotagmin plays a role in causing a conformational change in SNARE interactions similar to the change caused by calcium.[4] This binding of calcium-bound synaptotagmin creates an interaction that releases the fusion clamp of complexin, causing membrane fusion and exocytosis to occur.[9]

  • Calcium Effects

In low levels of calcium, complexin has a comparatively stronger clamping and inhibitory effect on spontaneous vesicle release. This is thought to be countered by synaptotagmin at increasing calcium levels, as the activity of synaptotagmin increases, providing more energy to remove the clamping effect of complexin.[4]

Complexin Acts to Promote Fusion

Complexin can also promote fusion when a stimulus is transmitted to the synapse. Independent of its clamping functionality (such as when the C-terminal of complexin is knocked out), complexin can still function as an exocytosis promoter.[10] This pathway is mediated by synaptotagmin-10 [11]

Association with Synaptotagmin

Complexin knockdown experiments have been linked to Synaptotagmin-1 and -10 dependent exocytosis. Both Synaptotagmin proteins seem reliant on a complexin co-factor, indicating complexin's importance across the synaptotagmin family.[11]

Genes

See also

References

  1. ^ Krishnakumar, Shyam; Radoff, Daniel; Kuemmel, Daniel; Giraudo, Claudio; Li, Feng; Khandan, Lavan; Wood Baguely, Stephanie; Coleman, Jeff; Reinisch, Karin; Pincet, Frederic; Rothman, James (August 2011). "A conformational switch in complexin is required for synaptotagmin to trigger synaptic fusion". Nature Structural & Molecular Biology. 18 (8): 934–940. doi:10.1038/nsmb.2103. PMC 3668341. PMID 21785412.
  2. ^ a b Hu K, Carroll J, Rickman C, Davletov B (2002). "Action of complexin on SNARE complex". J Biol Chem. 277 (44): 41652–6. doi:10.1074/jbc.M205044200. PMID 12200427.
  3. ^ Ishizuka T, Saisu H, Odani S, Abe T (1995). "Synaphin: a protein associated with the docking/fusion complex in presynaptic terminals". Biochem Biophys Res Commun. 213 (3): 1107–14. doi:10.1006/bbrc.1995.2241. PMID 7654227.
  4. ^ a b c d Jorquera, R. A.; Huntwork-Rodriguez, S.; Akbergenova, Y.; Cho, R. W.; Littleton, J. T. (2012). "Complexin Controls Spontaneous and Evoked Neurotransmitter Release by Regulating the Timing and Properties of Synaptotagmin Activity". Journal of Neuroscience. 32 (50): 18234–18245. doi:10.1523/JNEUROSCI.3212-12.2012. PMC 3530744. PMID 23238737.
  5. ^ Wragg, R. T.; Snead, D.; Dong, Y.; Ramlall, T. F.; Menon, I.; Bai, J.; Eliezer, D.; Dittman, J. S. (2013). "Synaptic Vesicles Position Complexin to Block Spontaneous Fusion". Neuron. 77 (2): 323–334. doi:10.1016/j.neuron.2012.11.005. PMC 3559010. PMID 23352168.
  6. ^ Hobson, R. J.; Liu, Q.; Watanabe, S.; Jorgensen, E. M. (2011). "Complexin Maintains Vesicles in the Primed State in C. Elegans". Current Biology. 21 (2): 106–113. doi:10.1016/j.cub.2010.12.015. PMC 3048763. PMID 21215631.
  7. ^ a b Kümmel, D.; Krishnakumar, S. S.; Radoff, D. T.; Li, F.; Giraudo, C. G.; Pincet, F.; Rothman, J. E.; Reinisch, K. M. (2011). "Complexin cross-links prefusion SNAREs into a zigzag array". Nature Structural & Molecular Biology. 18 (8): 927–933. doi:10.1038/nsmb.2101. PMC 3410656. PMID 21785414.
  8. ^ Giraudo, C. G.; Garcia-Diaz, A.; Eng, W. S.; Chen, Y.; Hendrickson, W. A.; Melia, T. J.; Rothman, J. E. (2009). "Alternative Zippering as an On-Off Switch for SNARE-Mediated Fusion". Science. 323 (5913): 512–516. Bibcode:2009Sci...323..512G. doi:10.1126/science.1166500. PMC 3736854. PMID 19164750.
  9. ^ Maximov, A.; Tang, J.; Yang, X.; Pang, Z. P.; Sudhof, T. C. (2009). "Complexin Controls the Force Transfer from SNARE Complexes to Membranes in Fusion". Science. 323 (5913): 516–521. Bibcode:2009Sci...323..516M. doi:10.1126/science.1166505. PMC 3235366. PMID 19164751.
  10. ^ Martin, J. A.; Hu, Z.; Fenz, K. M.; Fernandez, J.; Dittman, J. S. (2011). "Complexin Has Opposite Effects on Two Modes of Synaptic Vesicle Fusion". Current Biology. 21 (2): 97–105. doi:10.1016/j.cub.2010.12.014. PMC 3026084. PMID 21215634.
  11. ^ a b Cao, P.; Yang, X.; Sudhof, T. C. (2013). "Complexin Activates Exocytosis of Distinct Secretory Vesicles Controlled by Different Synaptotagmins". Journal of Neuroscience. 33 (4): 1714–1727. doi:10.1523/JNEUROSCI.4087-12.2013. PMC 3711587. PMID 23345244.

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This is the Wikipedia entry entitled "Synaphin protein domain". More...

Synaphin protein domain Edit Wikipedia article

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This page is based on a Wikipedia article. The text is available under the Creative Commons Attribution/Share-Alike License.

This tab holds the annotation information that is stored in the Pfam database. As we move to using Wikipedia as our main source of annotation, the contents of this tab will be gradually replaced by the Wikipedia tab.

Synaphin protein Provide feedback

This family consists of several eukaryotic synaphin 1 and 2 proteins. Synaphin/complexin is a cytosolic protein that preferentially binds to syntaxin within the SNARE complex. Synaphin promotes SNAREs to form precomplexes that oligomerise into higher order structures. A peptide from the central, syntaxin binding domain of synaphin competitively inhibits these two proteins from interacting and prevents SNARE complexes from oligomerising. It is thought that oligomerisation of SNARE complexes into a higher order structure creates a SNARE scaffold for efficient, regulated fusion of synaptic vesicles [1]. Synaphin promotes neuronal exocytosis by promoting interaction between the complementary syntaxin and synaptobrevin transmembrane regions that reside in opposing membranes prior to fusion [2].

Literature references

  1. Tokumaru H, Umayahara K, Pellegrini LL, Ishizuka T, Saisu H, Betz H, Augustine GJ, Abe T; , Cell 2001;104:421-432.: SNARE complex oligomerization by synaphin/complexin is essential for synaptic vesicle exocytosis. PUBMED:11239399 EPMC:11239399

  2. Hu K, Carroll J, Rickman C, Davletov B; , J Biol Chem 2002;277:41652-41656.: Action of complexin on SNARE complex. PUBMED:12200427 EPMC:12200427


External database links

This tab holds annotation information from the InterPro database.

InterPro entry IPR008849

This family consists of several eukaryotic synaphin 1 and 2 proteins. Synaphin/complexin is a cytosolic protein that preferentially binds to syntaxin within the SNARE complex. Synaphin promotes SNAREs to form precomplexes that oligomerise into higher order structures. A peptide from the central, syntaxin binding domain of synaphin competitively inhibits these two proteins from interacting and prevents SNARE complexes from oligomerising. It is thought that oligomerisation of SNARE complexes into a higher order structure creates a SNARE scaffold for efficient, regulated fusion of synaptic vesicles [ PUBMED:11239399 ]. Synaphin promotes neuronal exocytosis by promoting interaction between the complementary syntaxin and synaptobrevin transmembrane regions that reside in opposing membranes prior to fusion [ PUBMED:12200427 ].

Gene Ontology

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Domain organisation

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  Seed
(22)
Full
(1768)
Representative proteomes UniProt
(3233)
RP15
(257)
RP35
(635)
RP55
(1348)
RP75
(1803)
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  Seed
(22)
Full
(1768)
Representative proteomes UniProt
(3233)
RP15
(257)
RP35
(635)
RP55
(1348)
RP75
(1803)
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  Seed
(22)
Full
(1768)
Representative proteomes UniProt
(3233)
RP15
(257)
RP35
(635)
RP55
(1348)
RP75
(1803)
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Curation and family details

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Curation View help on the curation process

Seed source: Pfam-B_8588 (release 8.0)
Previous IDs: none
Type: Family
Sequence Ontology: SO:0100021
Author: Moxon SJ
Number in seed: 22
Number in full: 1768
Average length of the domain: 120.10 aa
Average identity of full alignment: 39 %
Average coverage of the sequence by the domain: 83.01 %

HMM information View help on HMM parameters

HMM build commands:
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 61295632 -E 1000 --cpu 4 HMM pfamseq
Model details:
Parameter Sequence Domain
Gathering cut-off 27.0 27.0
Trusted cut-off 27.2 27.1
Noise cut-off 25.6 26.6
Model length: 142
Family (HMM) version: 15
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Structures

For those sequences which have a structure in the Protein DataBank, we use the mapping between UniProt, PDB and Pfam coordinate systems from the PDBe group, to allow us to map Pfam domains onto UniProt sequences and three-dimensional protein structures. The table below shows the structures on which the Synaphin domain has been found. There are 13 instances of this domain found in the PDB. Note that there may be multiple copies of the domain in a single PDB structure, since many structures contain multiple copies of the same protein sequence.

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