Q4KUS2

SS
Gene name
Unc13a
Protein name
Protein unc-13 homolog A
Names
Munc13-1
Species
Mus musculus (Mouse)
KEGG Pathway
mmu:382018
EC number
Protein Class

Descriptions

Unc13, a phorbol ester/diacylglycerol-binding protein, is a synaptic hub protein required for fast chemical synaptic transmission by directly regulating SNAREs, and its Syntaxin-interacting MUN domain is essential for Unc13 function. The C1-C2B domain N-terminally adjacent to the MUN domain inhibits Unc13 function by tightly coupled to the MUN domain, which is disinhibited by diacylglycerol (DAG) or calcium binding. The disinhibition step allows for the superpriming of synaptic vesicles. Also, the addition of flexibility to the linker between the C2B and MUN domains relieves the autoinhibited state.

Autoinhibitory domains (AIDs)

563-612 (C1 domain) SS

Target domain

1002-1521 (MUN domain)

Relief mechanism

Ligand binding

Assay

668-796 (C2B domain) SS

Target domain

1002-1521 (MUN domain)

Relief mechanism

Ligand binding

Assay

797-1001 (C2B-MUN linker region) SS

Target domain

1002-1521 (MUN domain)

Relief mechanism

Ligand binding

Assay

Accessory elements

No accessory elements

References

Autoinhibited structure

Activated structure

6 structures for Q4KUS2

Entry ID Method Resolution Chain Position Source
7T7C EM 1000 A PDB
7T7R EM 1000 A PDB
7T7V EM 1000 A PDB
7T7X EM 1000 A PDB
7T81 EM 1000 A PDB
AF-Q4KUS2-F1 Predicted AlphaFoldDB

69 variants for Q4KUS2

Variant ID(s) Position Change Description Diseaes Association Provenance
rs3388990900 37 A>V No EVA
rs3388942551 100 D>Y No EVA
rs3399224125 160 Q>P No EVA
rs3388990881 174 C>Y No EVA
rs3399238502 209 P>S No EVA
rs3399234377 210 P>L No EVA
rs3388966663 217 Q>H No EVA
rs3388991191 342 E>G No EVA
rs3388988665 342 E>K No EVA
rs3388977658 346 E>K No EVA
rs3399238518 381 F>V No EVA
rs3388991121 386 F>I No EVA
rs3388988476 393 K>* No EVA
rs3399066908 418 E>* No EVA
rs3388966614 438 F>V No EVA
rs3398787358 447 Q>LDLLGRG* No EVA
rs3388987343 447 Q>R No EVA
rs3388984322 465 N>Y No EVA
rs3388995127 473 E>* No EVA
rs3388960252 475 R>E* No EVA
rs3388972092 477 E>* No EVA
rs3388987350 477 E>D No EVA
rs108187400 479 D>E No EVA
rs3388942530 497 I>N No EVA
rs3412959442 525 A>S No EVA
rs3388995144 547 K>M No EVA
rs3388977671 551 Q>* No EVA
rs3388966667 719 K>T No EVA
rs3388988672 741 H>N No EVA
rs3388984310 757 D>E No EVA
rs3388960286 759 K>N No EVA
rs3388972130 777 T>I No EVA
rs3388972093 796 K>N No EVA
rs3388996005 803 V>A No EVA
rs3399308784 806 A>V No EVA
rs3388991168 852 D>G No EVA
rs3388972085 861 V>A No EVA
rs3388991333 880 V>I No EVA
rs3399308751 888 T>S No EVA
rs3388995184 890 F>S No EVA
rs3388966574 912 N>K No EVA
rs3388988465 920 T>I No EVA
rs3388966628 927 S>Y No EVA
rs3388966600 1005 V>L No EVA
rs3388942597 1015 S>Y No EVA
rs3388988399 1017 Y>* No EVA
rs3388995155 1096 M>I No EVA
rs3399308763 1128 K>N No EVA
rs3399308754 1128 K>T No EVA
rs3399446594 1129 V>L No EVA
rs3388942577 1159 I>V No EVA
rs3388942557 1205 L>F No EVA
rs3388988670 1242 A>E No EVA
rs3388983744 1265 M>L No EVA
rs3388984270 1277 K>E No EVA
rs3388991331 1386 E>Q No EVA
rs3388983689 1395 M>L No EVA
rs3388966601 1425 R>K No EVA
rs3388991199 1425 R>S No EVA
rs3388988452 1436 Q>L No EVA
rs3388995143 1444 E>K No EVA
rs3388993935 1462 S>I No EVA
rs3388983571 1470 V>F No EVA
rs3388987352 1485 G>V No EVA
rs3388984244 1516 L>M No EVA
rs3388983684 1567 K>N No EVA
rs3388991374 1621 P>T No EVA
rs3388991361 1637 R>C No EVA
rs3388990905 1695 K>M No EVA

No associated diseases with Q4KUS2

8 regional properties for Q4KUS2

Type Name Position InterPro Accession
domain C2 domain 1 - 98 IPR000008-1
domain C2 domain 668 - 794 IPR000008-2
domain C2 domain 1535 - 1664 IPR000008-3
domain Protein kinase C-like, phorbol ester/diacylglycerol-binding domain 562 - 612 IPR002219
domain MUN domain 1002 - 1521 IPR010439
domain Munc13 homology 1 1102 - 1245 IPR014770
domain Mammalian uncoordinated homology 13, domain 2 1354 - 1521 IPR014772
domain Protein Unc-13, C2B domain 685 - 811 IPR037302

Functions

Description
EC Number
Subcellular Localization
  • Cytoplasm
  • Cell membrane ; Peripheral membrane protein
  • Presynaptic cell membrane ; Peripheral membrane protein
  • Presynaptic active zone
  • Translocated to the plasma membrane in response to phorbol ester binding
PANTHER Family
PANTHER Subfamily
PANTHER Protein Class
PANTHER Pathway Category No pathway information available

17 GO annotations of cellular component

Name Definition
axon The long process of a neuron that conducts nerve impulses, usually away from the cell body to the terminals and varicosities, which are sites of storage and release of neurotransmitter.
calyx of Held The terminal specialization of a calyciferous axon which forms large synapses in the mammalian auditory central nervous system.
excitatory synapse A synapse in which an action potential in the presynaptic cell increases the probability of an action potential occurring in the postsynaptic cell.
glutamatergic synapse A synapse that uses glutamate as a neurotransmitter.
Golgi-associated vesicle Any vesicle associated with the Golgi complex and involved in mediating transport within the Golgi or between the Golgi and other parts of the cell.
neuromuscular junction The junction between the axon of a motor neuron and a muscle fiber. In response to the arrival of action potentials, the presynaptic button releases molecules of neurotransmitters into the synaptic cleft. These diffuse across the cleft and transmit the signal to the postsynaptic membrane of the muscle fiber, leading to a change in post-synaptic potential.
neuron projection A prolongation or process extending from a nerve cell, e.g. an axon or dendrite.
plasma membrane The membrane surrounding a cell that separates the cell from its external environment. It consists of a phospholipid bilayer and associated proteins.
presynapse The part of a synapse that is part of the presynaptic cell.
presynaptic active zone A specialized region of the plasma membrane and cell cortex of a presynaptic neuron; encompasses a region of the plasma membrane where synaptic vesicles dock and fuse, and a specialized cortical cytoskeletal matrix.
presynaptic active zone cytoplasmic component A specialized region below the presynaptic membrane, characterized by electron-dense material, a specialized cytoskeletal matrix and accumulated (associated) synaptic vesicles.
presynaptic membrane A specialized area of membrane of the axon terminal that faces the plasma membrane of the neuron or muscle fiber with which the axon terminal establishes a synaptic junction; many synaptic junctions exhibit structural presynaptic characteristics, such as conical, electron-dense internal protrusions, that distinguish it from the remainder of the axon plasma membrane.
protein-containing complex A stable assembly of two or more macromolecules, i.e. proteins, nucleic acids, carbohydrates or lipids, in which at least one component is a protein and the constituent parts function together.
synapse The junction between an axon of one neuron and a dendrite of another neuron, a muscle fiber or a glial cell. As the axon approaches the synapse it enlarges into a specialized structure, the presynaptic terminal bouton, which contains mitochondria and synaptic vesicles. At the tip of the terminal bouton is the presynaptic membrane; facing it, and separated from it by a minute cleft (the synaptic cleft) is a specialized area of membrane on the receiving cell, known as the postsynaptic membrane. In response to the arrival of nerve impulses, the presynaptic terminal bouton secretes molecules of neurotransmitters into the synaptic cleft. These diffuse across the cleft and transmit the signal to the postsynaptic membrane.
synaptic membrane A specialized area of membrane on either the presynaptic or the postsynaptic side of a synapse, the junction between a nerve fiber of one neuron and another neuron or muscle fiber or glial cell.
synaptic vesicle membrane The lipid bilayer surrounding a synaptic vesicle.
terminal bouton Terminal inflated portion of the axon, containing the specialized apparatus necessary to release neurotransmitters. The axon terminus is considered to be the whole region of thickening and the terminal bouton is a specialized region of it.

11 GO annotations of molecular function

Name Definition
calcium ion binding Binding to a calcium ion (Ca2+).
calmodulin binding Binding to calmodulin, a calcium-binding protein with many roles, both in the calcium-bound and calcium-free states.
diacylglycerol binding Binding to a diacylglycerol, a diester of glycerol and two fatty acids.
identical protein binding Binding to an identical protein or proteins.
phospholipid binding Binding to a phospholipid, a class of lipids containing phosphoric acid as a mono- or diester.
protein domain specific binding Binding to a specific domain of a protein.
protein-containing complex binding Binding to a macromolecular complex.
SNARE binding Binding to a SNARE (soluble N-ethylmaleimide-sensitive factor attached protein receptor) protein.
spectrin binding Binding to spectrin, a protein that is the major constituent of the erythrocyte cytoskeletal network. It associates with band 4.1 (see band protein) and actin to form the cytoskeletal superstructure of the erythrocyte plasma membrane. It is composed of nonhomologous chains, alpha and beta, which aggregate side-to-side in an antiparallel fashion to form dimers, tetramers, and higher polymers.
syntaxin binding Binding to a syntaxin, a SNAP receptor involved in the docking of synaptic vesicles at the presynaptic zone of a synapse.
syntaxin-1 binding Binding to a syntaxin-1 SNAP receptor.

20 GO annotations of biological process

Name Definition
amyloid-beta metabolic process The chemical reactions and pathways involving amyloid-beta, a glycoprotein associated with Alzheimer's disease, and its precursor, amyloid precursor protein (APP).
cell differentiation The cellular developmental process in which a relatively unspecialized cell, e.g. embryonic or regenerative cell, acquires specialized structural and/or functional features that characterize a specific cell. Differentiation includes the processes involved in commitment of a cell to a specific fate and its subsequent development to the mature state.
dense core granule priming A process that converts unprimed dense core granules (DCVs) to a pool of primed vesicles that are capable of fusing with the plasma membrane (fusion-competent) and thereby releasing their contents. Priming typically occurs after docking.
innervation The process in which a nerve invades a tissue and makes functional synaptic connection within the tissue.
long-term synaptic potentiation A process that modulates synaptic plasticity such that synapses are changed resulting in the increase in the rate, or frequency of synaptic transmission at the synapse.
neuromuscular junction development A process that is carried out at the cellular level which results in the assembly, arrangement of constituent parts, or disassembly of a neuromuscular junction.
neuronal dense core vesicle exocytosis The secretion of molecules (e.g. neuropeptides, insulin-related peptides or neuromodulators such as serotonin and dopamine) contained within a neuronal dense core vesicle by fusion of the granule with the plasma membrane of a neuron in response to increased cytosolic calcium levels.
neurotransmitter secretion The regulated release of neurotransmitter from the presynapse into the synaptic cleft via calcium-regulated exocytosis during synaptic transmission.
positive regulation of glutamate receptor signaling pathway Any process that activates or increases the frequency, rate or extent of glutamate receptor signaling pathway.
positive regulation of neurotransmitter secretion Any process that activates or increases the frequency, rate or extent of the regulated release of a neurotransmitter.
positive regulation of synaptic plasticity A process that increases synaptic plasticity, the ability of synapses to change as circumstances require. They may alter function, such as increasing or decreasing their sensitivity, or they may increase or decrease in actual numbers.
presynaptic dense core vesicle exocytosis The secretion of molecules (e.g. neuropeptides and neuromodulators such as serotonin and dopamine) contained within a membrane-bounced dense in response to increased presynaptic cytosolic calcium levels.
regulation of amyloid precursor protein catabolic process Any process that modulates the frequency, rate or extent of amyloid precursor protein catabolic process.
regulation of short-term neuronal synaptic plasticity A process that modulates short-term neuronal synaptic plasticity, the ability of neuronal synapses to change in the short-term as circumstances require. Short-term neuronal synaptic plasticity generally involves increasing or decreasing synaptic sensitivity.
regulation of synaptic vesicle priming Any process that modulates the frequency, rate or extent of synaptic vesicle priming. Synaptic vesicle priming is the formation of SNARE-containing complexes, bringing synaptic vesicle membrane and plasma membranes into close proximity and thereby facilitating membrane fusion.
synaptic transmission, glutamatergic The vesicular release of glutamate from a presynapse, across a chemical synapse, the subsequent activation of glutamate receptors at the postsynapse of a target cell (neuron, muscle, or secretory cell) and the effects of this activation on the postsynaptic membrane potential and ionic composition of the postsynaptic cytosol. This process encompasses both spontaneous and evoked release of neurotransmitter and all parts of synaptic vesicle exocytosis. Evoked transmission starts with the arrival of an action potential at the presynapse.
synaptic vesicle docking The initial (indirect) attachment of a synaptic vesicle membrane to the presynaptic active zone membrane, mediated by proteins protruding from the membrane and proteins of the presynaptic active zone cytoplasmic component. Synaptic vesicle tethering is the first step in this process.
synaptic vesicle exocytosis Fusion of intracellular membrane-bounded vesicles with the pre-synaptic membrane of the neuronal cell resulting in release of neurotransmitter into the synaptic cleft.
synaptic vesicle maturation Steps required to form an initiated synaptic vesicle into a fully formed and transmissible synaptic vesicle.
synaptic vesicle priming A process that converts synaptic vesicles to a state of competence for calcium triggered fusion with the active zone membrane by bringing the two membranes into very close proximity. Priming typically (but not always) occurs after docking (Jahn and Fasshauer, 2012). Primed vesicles are also capable of spontaneously fusing with the active zone membrane.

9 homologous proteins in AiPD

UniProt AC Gene Name Protein Name Species Evidence Code
O14795 UNC13B Protein unc-13 homolog B Homo sapiens (Human) SS
Q8NB66 UNC13C Protein unc-13 homolog C Homo sapiens (Human) SS
Q9UPW8 UNC13A Protein unc-13 homolog A Homo sapiens (Human) SS
Q8K0T7 Unc13c Protein unc-13 homolog C Mus musculus (Mouse) SS
Q9Z1N9 Unc13b Protein unc-13 homolog B Mus musculus (Mouse) SS
Q62770 Unc13c Protein unc-13 homolog C Rattus norvegicus (Rat) SS
Q62769 Unc13b Protein unc-13 homolog B Rattus norvegicus (Rat) SS
Q62768 Unc13a Protein unc-13 homolog A Rattus norvegicus (Rat) SS
P27715 unc-13 Phorbol ester/diacylglycerol-binding protein unc-13 Caenorhabditis elegans EV
10 20 30 40 50 60
MSLLCVGVKK AKFDGAQEKF NTYVTLKVQN VKSTTIAVRG SQPSWEQDFM FEINRLDLGL
70 80 90 100 110 120
TVEVWNKGLI WDTMVGTVWI PLRTIRQSNE EGPGEWLTLD SQAIMADSEI CGTKDPTFHR
130 140 150 160 170 180
ILLDAHFELP LDIPEEEARY WAKKLEQLNA MRDQDEYSFQ DQQDKPLPVP SSQCCNWNYF
190 200 210 220 230 240
GWGEQNDDPD SAVDDRDSDY RSETSNSIPP PYYTTSQPNA SVHQYSVRPP PLGSRESYSD
250 260 270 280 290 300
SMHSYEEFSE PRALSPTGSS RYASSGELSQ GSSQLSEDFD PDEHSLQGSE LDDERDRDSY
310 320 330 340 350 360
HSCHSSVSYH KDSPRWDQDD EDLEDLEDLE DEELPEEEEE LEEEGEEELE EEDLEEEEEV
370 380 390 400 410 420
PDDLASYTQQ EDTTVAEPKE FKRISFPTAA PQKDDKVSAV PTEAPEVAKG IPKAATPEEK
430 440 450 460 470 480
AAAERAQEAE PPKSEESFRS REEEEGQEGQ DAMSRAKANW LRAFNKVRMQ LQEARGEGDM
490 500 510 520 530 540
SKSLWFKGGP GGGLIIIDSM PDIRKRKPIP LVSDLAMSLV QSRKAGITSA LASSTLNNEE
550 560 570 580 590 600
LKNHVYKKTL QALIYPISCT TPHNFEVWTA TTPTYCYECE GLLWGIARQG MRCTECGVKC
610 620 630 640 650 660
HEKCQDLLNA DCLQRAAEKS SKHGAEDRTQ NIIMVLKDRM KIRERNKPEI FELIQEIFAV
670 680 690 700 710 720
TKSAHTQQMK AVKQSVLDGT SKWSAKISIT VVCAQGLQAK DKTGSSDPYV TVQVGKTKKR
730 740 750 760 770 780
TKTIYGNLNP VWEENFHFEC HNSSDRIKVR VWDEDDDIKS RVKQRFKRES DDFLGQTIIE
790 800 810 820 830 840
VRTLSGEMDV WYNLDKRTDK SAVSGAIRLH ISVEIKGEEK VAPYHVQYTC LHENLFHFVT
850 860 870 880 890 900
DVQNNGVVKI PDAKGDDAWK VYYDETAQEI VDEFAMRYGV ESIYQAMTHF ACLSSKYMCP
910 920 930 940 950 960
GVPAVMSTLL ANINAYYAHT TASTNVSASD RFAASNFGKE RFVKLLDQLH NSLRIDLSMY
970 980 990 1000 1010 1020
RNNFPASSPE RLQDLKSTVD LLTSITFFRM KVQELQSPPR ASQVVKDCVK ACLNSTYEYI
1030 1040 1050 1060 1070 1080
FNNCHELYGR EYQTDPAKKG EVPPEEQGPS IKNLDFWSKL ITLIVSIIEE DKNSYTPCLN
1090 1100 1110 1120 1130 1140
QFPQELNVGK ISAEVMWSLF AQDMKYAMEE HDKHRLCKSA DYMNLHFKVK WLYNEYVAEL
1150 1160 1170 1180 1190 1200
PTFKDRVPEY PAWFEPFVIQ WLDENEEVSR DFLHGALERD KKDGFQQTSE HALFSCSVVD
1210 1220 1230 1240 1250 1260
VFSQLNQSFE IIKKLECPDP QIVGHYMRRF AKTISNVLLQ YADIVSKDFA SYCSKEKEKV
1270 1280 1290 1300 1310 1320
PCILMNNTQQ LRVQLEKMFE AMGGKELDAE ASGTLKELQV KLNNVLDELS HVFATSFQPH
1330 1340 1350 1360 1370 1380
IEECVRQMGD ILSQVKGTGN VPASACSSVA QDADNVLQPI MDLLDSNLTL FAKICEKTVL
1390 1400 1410 1420 1430 1440
KRVLKELWKL VMNTMEKTIV LPPLTDQTMI GTLLRKHGKG LEKGRVKLPS HSDGTQMIFN
1450 1460 1470 1480 1490 1500
AAKELGQLSK LKDHMVREEA KSLTPKQCAV VELALDTIKQ YFHAGGVGLK KTFLEKSPDL
1510 1520 1530 1540 1550 1560
QSLRYALSLY TQATDLLIKT FVQTQSAQGS GVEDPVGEVS VHVELFTHPG TGEQKVTVKV
1570 1580 1590 1600 1610 1620
VAANDLKWQT SGIFRPFIEV NIVGPQLSDK KRKFATKSKN NSWAPKYNES FQFSLSADAG
1630 1640 1650 1660 1670 1680
PECYELQVCV KDYCFAREDR TVGLAVLQLR ELAQRGSAAC WLPLGRRIHM DDTGLTVLRI
1690 1700 1710
LSQRSNDEVA KEFVKLKSDT RSAEEGGAAP AP