Complexin

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Synaphin
PDB 1kil EBI.jpg
3-D structure of the Complexin/SNARE complex
Identifiers
SymbolSynaphin
Pfam PF05835
InterPro IPR008849
SCOPe 1l4a / 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.

Contents

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]

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

Related Research Articles

Exocytosis Process of active transport by which a cell secretes intracellular molecules contained within a membrane-bound vesicle

Exocytosis is a form of active transport and bulk transport in which a cell transports molecules out of the cell by secreting them through an energy-dependent process. Exocytosis and its counterpart, endocytosis, are used by all cells because most chemical substances important to them are large polar molecules that cannot pass through the hydrophobic portion of the cell membrane by passive means. Exocytosis is in process a large amount of molecules are released thus making it a form of bulk transport.

Synaptic vesicle Neurotransmitters that are released at the synapse

In a neuron, synaptic vesicles store various neurotransmitters that are released at the synapse. The release is regulated by a voltage-dependent calcium channel. Vesicles are essential for propagating nerve impulses between neurons and are constantly recreated by the cell. The area in the axon that holds groups of vesicles is an axon terminal or "terminal bouton". Up to 130 vesicles can be released per bouton over a ten-minute period of stimulation at 0.2 Hz. In the visual cortex of the human brain, synaptic vesicles have an average diameter of 39.5 nanometers (nm) with a standard deviation of 5.1 nm.

SNARE (protein) family of proteins involved in vesicle fusion

SNARE proteins — "SNAPREceptor" — are a large protein family consisting of at least 24 members in yeasts and more than 60 members in mammalian cells. The primary role of SNARE proteins is to mediate vesicle fusion – the fusion of vesicles with the target membrane; this notably mediates exocytosis, but can also mediate the fusion of vesicles with membrane-bound compartments. The best studied SNAREs are those that mediate the neurotransmitter release of synaptic vesicles in neurons. These neuronal SNAREs are the targets of the neurotoxins responsible for botulism and tetanus produced by certain bacteria.

Synaptobrevin protein family

Synaptobrevins are small integral membrane proteins of secretory vesicles with molecular weight of 18 kilodalton (kDa) that are part of the vesicle-associated membrane protein (VAMP) family.

SNAP25 protein-coding gene in the species Homo sapiens

Synaptosomal-Associated Protein, 25kDa (SNAP-25) is a t-SNARE protein that is encoded by the SNAP25 gene in humans. SNAP-25 is a component of the trans-SNARE complex, which is proposed to account for the specificity of membrane fusion and to directly execute fusion by forming a tight complex that brings the synaptic vesicle and plasma membranes together.

Synaptotagmin chemical compound

Synaptotagmins (SYTs) constitute a family of membrane-trafficking proteins that are characterized by an N-terminal transmembrane region (TMR), a variable linker, and two C-terminal C2 domains - C2A and C2B. There are 17 isoforms in the mammalian synaptotagmin family. There are several C2-domain containing protein families that are related to synaptotagmins, including transmembrane (Ferlins, Extended-Synaptotagmin (E-Syt) membrane proteins, and MCTPs) and soluble (RIMS1 and RIMS2, UNC13D, synaptotagmin-related proteins and B/K) proteins. The family includes synaptotagmin 1, a Ca2+ sensor in the membrane of the pre-synaptic axon terminal, coded by gene SYT1.

STX1A protein-coding gene in the species Homo sapiens

Syntaxin-1A is a protein that in humans is encoded by the STX1A gene.

SYT1 protein-coding gene in the species Homo sapiens

Synaptotagmin-1 is a protein that in humans is encoded by the SYT1 gene.

VAMP2 protein-coding gene in the species Homo sapiens

Vesicle-associated membrane protein 2 is a protein that in humans is encoded by the VAMP2 gene.

CPLX2 protein-coding gene in the species Homo sapiens

Complexin-2 is a protein that in humans is encoded by the CPLX2 gene.

DNAJC5 protein-coding gene in the species Homo sapiens

DnaJ homolog subfamily C member 5, also known as cysteine string protein or CSP is a protein, that in humans encoded by the DNAJC5 gene. It was first described in 1990.

CPLX1 protein-coding gene in the species Homo sapiens

Complexin-1 is a protein that in humans is encoded by the CPLX1 gene.

The ribbon synapse is a type of neuronal synapse characterized by the presence of an electron-dense structure, the synaptic ribbon, that holds vesicles close to the active zone. It is characterized by a tight vesicle-calcium channel coupling that promotes rapid neurotransmitter release and sustained signal transmission. Ribbon synapses undergo a cycle of exocytosis and endocytosis in response to graded changes of membrane potential. It has been proposed that most ribbon synapses undergo a special type of exocytosis based on coordinated multivesicular release. This interpretation has recently been questioned at the inner hair cell ribbon synapse, where it has been instead proposed that exocytosis is described by uniquantal release shaped by a flickering vesicle fusion pore.

Syntaxin chemical compound

Syntaxins are a family of membrane integrated Q-SNARE proteins participating in exocytosis.

Vesicle fusion is the merging of a vesicle with other vesicles or a part of a cell membrane. In the latter case, it is the end stage of secretion from secretory vesicles, where their contents are expelled from the cell through exocytosis. Vesicles can also fuse with other target cell compartments, such as a lysosome. Exocytosis occurs when secretory vesicles transiently dock and fuse at the base of cup-shaped structures at the cell plasma membrane called porosome, the universal secretory machinery in cells. Vesicle fusion may depend on SNARE proteins in the presence of increased intracellular calcium (Ca2+) concentration.

Munc-18 proteins are the mammalian homologue of UNC-18 and are a member of the Sec1/Munc18-like (SM) protein family. Munc-18 proteins have been identified as essential components of the synaptic vesicle fusion protein complex and are crucial for the regulated exocytosis of neurons and neuroendocrine cells.

Thomas C. Südhof German biochemist

Thomas Christian Südhof, ForMemRS, is a German-American biochemist known for his study of synaptic transmission. Currently, he is a professor in the School of Medicine in the Department of Molecular and Cellular Physiology, and by courtesy in Neurology, and in Psychiatry and Behavioral Sciences at Stanford University.

Active zone

The active zone or synaptic active zone is a term first used by Couteaux and Pecot-Dechavassinein in 1970 to define the site of neurotransmitter release. Two neurons make near contact through structures called synapses allowing them to communicate with each other. As shown in the adjacent diagram, a synapse consists of the presynaptic bouton of one neuron which stores vesicles containing neurotransmitter, and a second, postsynaptic neuron which bears receptors for the neurotransmitter, together with a gap between the two called the synaptic cleft. When an action potential reaches the presynaptic bouton, the contents of the vesicles are released into the synaptic cleft and the released neurotransmitter travels across the cleft to the postsynaptic neuron and activates the receptors on the postsynaptic membrane.

Kiss-and-run fusion is a type of synaptic vesicle release where the vesicle opens and closes transiently. In this form of exocytosis, the vesicle docks and transiently fuses at the presynaptic membrane and releases its neurotransmitters across the synapse, after which the vesicle can then be reused.

Neurotransmitters are released into a synapse in packaged vesicles called quanta. One quantum generates what is known as a miniature end plate potential (MEPP) which is the smallest amount of stimulation that one neuron can send to another neuron. Quantal release is the mechanism by which most traditional endogenous neurotransmitters are transmitted throughout the body. The aggregate sum of many MEPPs is known as an end plate potential (EPP). A normal end plate potential usually causes the postsynaptic neuron to reach its threshold of excitation and elicit an action potential. Electrical synapses do not use quantal neurotransmitter release and instead use gap junctions between neurons to send current flows between neurons. The goal of any synapse is to produce either an excitatory postsynaptic potential (EPSP) or an inhibitory postsynaptic potential (IPSP), which generate or repress the expression, respectively, of an action potential in the postsynaptic neuron. It is estimated that an action potential will trigger the release of approximately 20% of an axon terminal's neurotransmitter load.

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. 1 2 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. 1 2 3 4 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. 1 2 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. 1 2 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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