Q9EQZ6
EV
Gene name |
Rapgef4 (Cgef2, Epac2) |
Protein name |
Rap guanine nucleotide exchange factor 4 |
Names |
Exchange factor directly activated by cAMP 2 , Exchange protein directly activated by cAMP 2 , EPAC 2 , cAMP-dependent Rap1 guanine-nucleotide exchange factor , cAMP-regulated guanine nucleotide exchange factor II , cAMP-GEFII |
Species |
Mus musculus (Mouse) |
KEGG Pathway |
mmu:56508 |
EC number |
|
Protein Class |
|
Descriptions
EPAC2, or Exchange Protein Directly Activated by cAMP, is a signaling molecule that acts as an intracellular sensor for cAMP, a second messenger. EPAC2’s autoinhibition is due to its compact, inactive conformation. Binding of cAMP induces conformational changes that activate EPAC2 by exposing its catalytic core, which then interacts with downstream effectors. The activity of EPAC2 is regulated by its conformational dynamics. Mutations can shift its dynamics, leading to constitutive activation even without cAMP.
Autoinhibitory domains (AIDs)
Target domain |
495-634 (REM domain) |
Relief mechanism |
Ligand binding |
Assay |
Structural analysis, Mutagenesis experiment |
Accessory elements
No accessory elements
Autoinhibited structure
Activated structure
10 structures for Q9EQZ6
| Entry ID | Method | Resolution | Chain | Position | Source |
|---|---|---|---|---|---|
| 1O7F | X-ray | 250 A | A | 1-481 | PDB |
| 2BYV | X-ray | 270 A | E | 1-1011 | PDB |
| 3CF6 | X-ray | 220 A | E | 324-1011 | PDB |
| 4F7Z | X-ray | 260 A | A | 1-1011 | PDB |
| 4MGI | X-ray | 280 A | E | 324-1011 | PDB |
| 4MGK | X-ray | 270 A | E | 324-1011 | PDB |
| 4MGY | X-ray | 260 A | E | 324-1011 | PDB |
| 4MGZ | X-ray | 300 A | E | 324-1011 | PDB |
| 4MH0 | X-ray | 240 A | E | 324-1011 | PDB |
| AF-Q9EQZ6-F1 | Predicted | AlphaFoldDB |
58 variants for Q9EQZ6
| Variant ID(s) | Position | Change | Description | Diseaes Association | Provenance |
|---|---|---|---|---|---|
| rs3388552810 | 34 | I>N | No | EVA | |
| rs27968319 | 65 | E>D | No | EVA | |
| rs3388561707 | 70 | L>Q | No | EVA | |
| rs3388558737 | 80 | W>C | No | EVA | |
| rs3388561764 | 81 | Y>F | No | EVA | |
| rs3388558246 | 99 | Q>R | No | EVA | |
| rs3388558293 | 104 | I>N | No | EVA | |
| rs3388549892 | 177 | K>M | No | EVA | |
| rs3391768063 | 197 | K>* | No | EVA | |
| rs3391723350 | 197 | K>M | No | EVA | |
| rs3388549832 | 272 | N>T | No | EVA | |
| rs3388562500 | 279 | H>L | No | EVA | |
| rs3388552853 | 304 | E>V | No | EVA | |
| rs3391739737 | 311 | E>D | No | EVA | |
| rs3391723402 | 311 | E>V | No | EVA | |
| rs3388558296 | 312 | L>F | No | EVA | |
| rs3391691480 | 313 | Q>H | No | EVA | |
| rs3391802045 | 314 | D>H | No | EVA | |
| rs3391662243 | 320 | S>L | No | EVA | |
| rs3388560451 | 346 | I>V | No | EVA | |
| rs3388554857 | 351 | L>I | No | EVA | |
| rs3388562535 | 389 | E>G | No | EVA | |
| rs3388558661 | 405 | V>F | No | EVA | |
| rs3391747014 | 413 | C>* | No | EVA | |
| rs3388560661 | 445 | F>S | No | EVA | |
| rs3388554564 | 465 | V>A | No | EVA | |
| rs3388556355 | 470 | H>N | No | EVA | |
| rs3388556319 | 477 | L>M | No | EVA | |
| rs3388561608 | 486 | A>T | No | EVA | |
| rs3388549851 | 534 | V>A | No | EVA | |
| rs3388562518 | 544 | T>I | No | EVA | |
| rs3388558711 | 545 | Q>K | No | EVA | |
| rs3388552799 | 549 | A>T | No | EVA | |
| rs3388561595 | 560 | Q>H | No | EVA | |
| rs3388554839 | 562 | T>I | No | EVA | |
| rs3388558243 | 564 | Q>E | No | EVA | |
| rs3388558463 | 570 | A>S | No | EVA | |
| rs3388549857 | 601 | F>V | No | EVA | |
| rs3391802028 | 602 | L>V | No | EVA | |
| rs3388558466 | 622 | Q>L | No | EVA | |
| rs3388558488 | 665 | R>H | No | EVA | |
| rs3388558696 | 681 | Y>H | No | EVA | |
| rs3388552850 | 736 | I>F | No | EVA | |
| rs3388559670 | 746 | E>A | No | EVA | |
| rs3391746959 | 771 | M>I | No | EVA | |
| rs3388559682 | 772 | S>T | No | EVA | |
| rs3391760202 | 774 | K>N | No | EVA | |
| rs3388561728 | 792 | H>L | No | EVA | |
| rs3388560647 | 823 | I>N | No | EVA | |
| rs3388560700 | 833 | L>P | No | EVA | |
| rs3388554851 | 861 | N>I | No | EVA | |
| rs3388561724 | 865 | A>S | No | EVA | |
| rs27951150 | 872 | N>K | No | EVA | |
| rs3388558733 | 876 | S>T | No | EVA | |
| rs3388558172 | 887 | S>G | No | EVA | |
| rs3388558758 | 912 | T>S | No | EVA | |
| rs3388559742 | 925 | P>T | No | EVA | |
| rs3388549881 | 944 | N>I | No | EVA |
No associated diseases with Q9EQZ6
25 regional properties for Q9EQZ6
| Type | Name | Position | InterPro Accession |
|---|---|---|---|
| domain | Protein kinase domain | 845 - 1173 | IPR000719 |
| domain | Serine-threonine/tyrosine-protein kinase, catalytic domain | 845 - 1169 | IPR001245 |
| conserved_site | Tyrosine-protein kinase, receptor class III, conserved site | 904 - 917 | IPR001824 |
| domain | Immunoglobulin subtype 2 | 243 - 317 | IPR003598-1 |
| domain | Immunoglobulin subtype 2 | 347 - 406 | IPR003598-2 |
| domain | Immunoglobulin subtype 2 | 569 - 660 | IPR003598-3 |
| domain | Immunoglobulin subtype 2 | 690 - 755 | IPR003598-4 |
| domain | Immunoglobulin subtype | 36 - 133 | IPR003599-1 |
| domain | Immunoglobulin subtype | 143 - 225 | IPR003599-2 |
| domain | Immunoglobulin subtype | 237 - 328 | IPR003599-3 |
| domain | Immunoglobulin subtype | 341 - 419 | IPR003599-4 |
| domain | Immunoglobulin subtype | 430 - 552 | IPR003599-5 |
| domain | Immunoglobulin subtype | 563 - 673 | IPR003599-6 |
| domain | Immunoglobulin subtype | 684 - 766 | IPR003599-7 |
| domain | Immunoglobulin-like domain | 30 - 111 | IPR007110-1 |
| domain | Immunoglobulin-like domain | 219 - 326 | IPR007110-2 |
| domain | Immunoglobulin-like domain | 331 - 415 | IPR007110-3 |
| domain | Immunoglobulin-like domain | 422 - 552 | IPR007110-4 |
| domain | Immunoglobulin-like domain | 555 - 671 | IPR007110-5 |
| domain | Immunoglobulin-like domain | 678 - 764 | IPR007110-6 |
| active_site | Tyrosine-protein kinase, active site | 1033 - 1045 | IPR008266 |
| domain | Immunoglobulin I-set | 678 - 765 | IPR013098 |
| binding_site | Protein kinase, ATP binding site | 851 - 879 | IPR017441 |
| domain | Tyrosine-protein kinase, catalytic domain | 845 - 1169 | IPR020635 |
| domain | VEGFR-2, transmembrane domain | 770 - 804 | IPR041348 |
18 GO annotations of cellular component
| Name | Definition |
|---|---|
| apical plasma membrane | The region of the plasma membrane located at the apical end of the cell. |
| 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. |
| basolateral plasma membrane | The region of the plasma membrane that includes the basal end and sides of the cell. Often used in reference to animal polarized epithelial membranes, where the basal membrane is the part attached to the extracellular matrix, or in plant cells, where the basal membrane is defined with respect to the zygotic axis. |
| brush border | The dense covering of microvilli on the apical surface of an epithelial cell in tissues such as the intestine, kidney, and choroid plexus; the microvilli aid absorption by increasing the surface area of the cell. |
| cone cell pedicle | A specialized axon terminus which is produced by retinal cone cells. Pedicles are large, conical, flat end-feet (8-10 micrometers diameter) of the retinal cone axon that lie more or less side by side on the same plane at the outer edge of the outer plexiform layer (OPL). |
| cytosol | The part of the cytoplasm that does not contain organelles but which does contain other particulate matter, such as protein complexes. |
| dendrite | A neuron projection that has a short, tapering, morphology. Dendrites receive and integrate signals from other neurons or from sensory stimuli, and conduct nerve impulses towards the axon or the cell body. In most neurons, the impulse is conveyed from dendrites to axon via the cell body, but in some types of unipolar neuron, the impulse does not travel via the cell body. |
| dendritic spine | A small, membranous protrusion from a dendrite that forms a postsynaptic compartment, typically receiving input from a single presynapse. They function as partially isolated biochemical and an electrical compartments. Spine morphology is variable:they can be thin, stubby, mushroom, or branched, with a continuum of intermediate morphologies. They typically terminate in a bulb shape, linked to the dendritic shaft by a restriction. Spine remodeling is though to be involved in synaptic plasticity. |
| 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. |
| growth cone | The migrating motile tip of a growing neuron projection, where actin accumulates, and the actin cytoskeleton is the most dynamic. |
| hippocampal mossy fiber to CA3 synapse | One of the giant synapses that form between the mossy fiber axons of dentate gyrus granule cells and the large complex spines of CA3 pyramidal cells. It consists of a giant bouton known as the mossy fiber expansion, synapsed to the complex, multiheaded spine (thorny excresence) of a CA3 pyramidal cell. |
| neuronal cell body | The portion of a neuron that includes the nucleus, but excludes cell projections such as axons and dendrites. |
| photoreceptor inner segment | The inner segment of a vertebrate photoreceptor containing mitochondria, ribosomes and membranes where opsin molecules are assembled and passed to be part of the outer segment discs. |
| photoreceptor outer segment | The outer segment of a vertebrate photoreceptor that contains a stack of membrane discs embedded with photoreceptor proteins. |
| plasma membrane | The membrane surrounding a cell that separates the cell from its external environment. It consists of a phospholipid bilayer and associated proteins. |
| postsynaptic density | An electron dense network of proteins within and adjacent to the postsynaptic membrane of an asymmetric, neuron-neuron synapse. Its major components include neurotransmitter receptors and the proteins that spatially and functionally organize them such as anchoring and scaffolding molecules, signaling enzymes and cytoskeletal components. |
| 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. |
5 GO annotations of molecular function
| Name | Definition |
|---|---|
| cAMP binding | Binding to cAMP, the nucleotide cyclic AMP (adenosine 3',5'-cyclophosphate). |
| guanyl-nucleotide exchange factor activity | Stimulates the exchange of GDP to GTP on a signaling GTPase, changing its conformation to its active form. Guanine nucleotide exchange factors (GEFs) act by stimulating the release of guanosine diphosphate (GDP) to allow binding of guanosine triphosphate (GTP), which is more abundant in the cell under normal cellular physiological conditions. |
| protein-containing complex binding | Binding to a macromolecular complex. |
| protein-macromolecule adaptor activity | The binding activity of a protein that brings together two or more macromolecules in contact, permitting those molecules to function in a coordinated way. The adaptor can bring together two proteins, or a protein and another macromolecule such as a lipid or a nucleic acid. |
| small GTPase binding | Binding to a small monomeric GTPase. |
16 GO annotations of biological process
| Name | Definition |
|---|---|
| adenylate cyclase-activating G protein-coupled receptor signaling pathway | A G protein-coupled receptor signaling pathway in which the signal is transmitted via the activation of adenylyl cyclase activity and a subsequent increase in the intracellular concentration of cyclic AMP (cAMP). |
| adenylate cyclase-modulating G protein-coupled receptor signaling pathway | A G protein-coupled receptor signaling pathway in which the signal is transmitted via the activation or inhibition of adenylyl cyclase activity and a subsequent change in the intracellular concentration of cyclic AMP (cAMP). |
| calcium-ion regulated exocytosis | The release of intracellular molecules (e.g. hormones, matrix proteins) contained within a membrane-bounded vesicle by fusion of the vesicle with the plasma membrane of a cell, induced by a rise in cytosolic calcium-ion levels. |
| hormone secretion | The regulated release of hormones, substances with a specific regulatory effect on a particular organ or group of cells. |
| insulin secretion | The regulated release of proinsulin from secretory granules accompanied by cleavage of proinsulin to form mature insulin. In vertebrates, insulin is secreted from B granules in the B cells of the vertebrate pancreas and from insulin-producing cells in insects. |
| negative regulation of synaptic transmission | Any process that stops, prevents, or reduces the frequency, rate or extent of synaptic transmission, the process of communication from a neuron to a target (neuron, muscle, or secretory cell) across a synapse. |
| positive regulation of insulin secretion | Any process that activates or increases the frequency, rate or extent of the regulated release of insulin. |
| positive regulation of neuronal action potential | Any process that activates or increases the frequency, rate or extent of neuronal action potential. |
| positive regulation of protein secretion | Any process that activates or increases the frequency, rate or extent of the controlled release of a protein from a cell. |
| positive regulation of smooth muscle cell migration | Any process that activates, maintains or increases the frequency, rate or extent of smooth muscle cell migration. |
| Ras protein signal transduction | The series of molecular signals within the cell that are mediated by a member of the Ras superfamily of proteins switching to a GTP-bound active state. |
| regulation of dendrite development | Any process that modulates the frequency, rate or extent of dendrite development. |
| regulation of exocytosis | Any process that modulates the frequency, rate or extent of exocytosis. |
| regulation of neurotransmitter receptor localization to postsynaptic specialization membrane | Any process that modulates the frequency, rate or extent of neurotransmitter receptor localization to postsynaptic specialization membrane. |
| regulation of postsynapse organization | Any process that modulates the physical form of a postsynapse. |
| regulation of synaptic vesicle cycle | Any process that modulates the frequency, rate or extent of the synaptic vesicle cycle. |
13 homologous proteins in AiPD
| UniProt AC | Gene Name | Protein Name | Species | Evidence Code |
|---|---|---|---|---|
| O95398 | RAPGEF3 | Rap guanine nucleotide exchange factor 3 | Homo sapiens (Human) | EV |
| Q8WZA2 | RAPGEF4 | Rap guanine nucleotide exchange factor 4 | Homo sapiens (Human) | SS |
| Q02384 | Sos2 | Son of sevenless homolog 2 | Mus musculus (Mouse) | SS |
| Q62245 | Sos1 | Son of sevenless homolog 1 | Mus musculus (Mouse) | SS |
| Q8VCC8 | Rapgef3 | Rap guanine nucleotide exchange factor 3 | Mus musculus (Mouse) | SS |
| Q9D300 | Rasgef1c | Ras-GEF domain-containing family member 1C | Mus musculus (Mouse) | PR |
| Q03385 | Ralgds | Ral guanine nucleotide dissociation stimulator | Mus musculus (Mouse) | PR |
| Q9Z1S3 | Rasgrp1 | RAS guanyl-releasing protein 1 | Mus musculus (Mouse) | SS |
| Q8BTM9 | Rasgrp4 | RAS guanyl-releasing protein 4 | Mus musculus (Mouse) | SS |
| Q9QUG9 | Rasgrp2 | RAS guanyl-releasing protein 2 | Mus musculus (Mouse) | SS |
| Q9ERD6 | Ralgps2 | Ras-specific guanine nucleotide-releasing factor RalGPS2 | Mus musculus (Mouse) | PR |
| A2AR50 | Ralgps1 | Ras-specific guanine nucleotide-releasing factor RalGPS1 | Mus musculus (Mouse) | PR |
| Q9Z1C8 | Rapgef3 | Rap guanine nucleotide exchange factor 3 | Rattus norvegicus (Rat) | SS |
| 10 | 20 | 30 | 40 | 50 | 60 |
| MVAAHAAHSQ | SSAEWIACLD | KRPLERSSED | VDIIFTRLKG | VKAFEKFHPN | LLRQICLCGY |
| 70 | 80 | 90 | 100 | 110 | 120 |
| YENLEKGITL | FRQGDIGTNW | YAVLAGSLDV | KVSETSSHQD | AVTICTLGIG | TAFGESILDN |
| 130 | 140 | 150 | 160 | 170 | 180 |
| TPRHATIVTR | ESSELLRIEQ | EDFKALWEKY | RQYMAGLLAP | PYGVMETGSN | NDRIPDKENT |
| 190 | 200 | 210 | 220 | 230 | 240 |
| PLIEPHVPLR | PAHTITKVPS | EKILRAGKIL | RIAILSRAPH | MIRDRKYHLK | TYRQCCVGTE |
| 250 | 260 | 270 | 280 | 290 | 300 |
| LVDWMIQQTS | CVHSRTQAVG | MWQVLLEDGV | LNHVDQERHF | QDKYLFYRFL | DDEREDAPLP |
| 310 | 320 | 330 | 340 | 350 | 360 |
| TEEEKKECDE | ELQDTMLLLS | QMGPDAHMRM | ILRKPPGQRT | VDDLEIIYDE | LLHIKALSHL |
| 370 | 380 | 390 | 400 | 410 | 420 |
| STTVKRELAG | VLIFESHAKG | GTVLFNQGEE | GTSWYIILKG | SVNVVIYGKG | VVCTLHEGDD |
| 430 | 440 | 450 | 460 | 470 | 480 |
| FGKLALVNDA | PRAASIVLRE | DNCHFLRVDK | EDFNRILRDV | EANTVRLKEH | DQDVLVLEKV |
| 490 | 500 | 510 | 520 | 530 | 540 |
| PAGNRAANQG | NSQPQQKYTV | MSGTPEKILE | HFLETIRLEP | SLNEATDSVL | NDFVMMHCVF |
| 550 | 560 | 570 | 580 | 590 | 600 |
| MPNTQLCPAL | VAHYHAQPSQ | GTEQERMDYA | LNNKRRVIRL | VLQWAAMYGD | LLQEDDVAMA |
| 610 | 620 | 630 | 640 | 650 | 660 |
| FLEEFYVSVS | DDARMMAAFK | EQLPELEKIV | KQISEDAKAP | QKKHKVLLQQ | FNTGDERAQK |
| 670 | 680 | 690 | 700 | 710 | 720 |
| RQPIRGSDEV | LFKVYCIDHT | YTTIRVPVAA | SVKEVISAVA | DKLGSGEGLI | IVKMNSGGEK |
| 730 | 740 | 750 | 760 | 770 | 780 |
| VVLKSNDVSV | FTTLTINGRL | FACPREQFDS | LTPLPEQEGP | TTGTVGTFEL | MSSKDLAYQM |
| 790 | 800 | 810 | 820 | 830 | 840 |
| TTYDWELFNC | VHELELIYHT | FGRHNFKKTT | ANLDLFLRRF | NEIQFWVVTE | VCLCSQLSKR |
| 850 | 860 | 870 | 880 | 890 | 900 |
| VQLLKKFIKI | AAHCKEYKNL | NSFFAIVMGL | SNVAVSRLAL | TWEKLPSKFK | KFYAEFESLM |
| 910 | 920 | 930 | 940 | 950 | 960 |
| DPSRNHRAYR | LTAAKLEPPL | IPFMPLLIKD | MTFTHEGNKT | FIDNLVNFEK | MRMIANTART |
| 970 | 980 | 990 | 1000 | 1010 | |
| VRYYRSQPFN | PDAAQANKNH | QDVRSYVRQL | NVIDNQRTLS | QMSHRLEPRR | P |