Descriptions
Ras regulation in B cells involves a Ras-guanyl nucleotide exchange factor. RasGRP, a member of the cdc25 family of Ras guanyl nucleotide exchange factors (Ras-GEFs), has a DAG-binding C1 domain, DAG generated upon antigen receptor stimulation contributes to recruiting RasGRP to the membrane, where it interacts with Ras. PKC, after being activated by diacylglycerol, phosphorylates RasGRP3, thereby contributing to the full activation of RasGRP3. Mutation of Thr-133 in the Cdc25 domain of RasGRP3 alone severely impairs its ability to activate Ras in B cell signaling, which represents an autoinhibition mechanism in RasGRP3. The Thr-133 site is conserved in human, mouse, and chicken.
In other RasGRP proteins, the phosphorylation of the Cdc25 domain could aid in removal of the inhibitory linker between Cdc25 and EF domain. Briefly, inactive RasGRP is stabilized by the C1-dimer interface, which sequesters the membrane-interacting surface of the C1 domain, and the active-site blocking RasGEF catalytic domain (Cdc25)-EF domain linker. The C-terminal coiled-coil stabilizes the dimer, thereby preventing inappropriate Ras activation. The autoinhibited form is activated by multiple signaling inputs that enhance nucleotide exchange activity. Diacylglycerol binding disrupts C1 dimerization, while Ca2+ binding to EF1 causes a conformational change that contributes to C1 reorientation, and the release of the inhibitory segment from the Ras-binding surface. Phosphorylation of the Cdc25 domain could aid in removal of the inhibitory linker.
Autoinhibitory domains (AIDs)
Target domain |
152-383 (RasGEF catalytic domain) |
Relief mechanism |
Ligand binding, PTM |
Assay |
|
Target domain |
421-485 (EF domain) |
Relief mechanism |
Ligand binding, PTM |
Assay |
|
Accessory elements
No accessory elements
References
- Aiba Y et al. (2004) "Activation of RasGRP3 by phosphorylation of Thr-133 is required for B cell receptor-mediated Ras activation", Proceedings of the National Academy of Sciences of the United States of America, 101, 16612-7
- Czikora A et al. (2016) "Structural Basis for the Failure of the C1 Domain of Ras Guanine Nucleotide Releasing Protein 2 (RasGRP2) to Bind Phorbol Ester with High Affinity", The Journal of biological chemistry, 291, 11133-47
- Canault M et al. (2020) "RasGRP2 Structure, Function and Genetic Variants in Platelet Pathophysiology", International journal of molecular sciences, 21,
Autoinhibited structure
Activated structure
1 structures for A0A3S5ZPR1
| Entry ID | Method | Resolution | Chain | Position | Source |
|---|---|---|---|---|---|
| AF-A0A3S5ZPR1-F1 | Predicted | AlphaFoldDB |
16 variants for A0A3S5ZPR1
| Variant ID(s) | Position | Change | Description | Diseaes Association | Provenance |
|---|---|---|---|---|---|
| rs735224762 | 68 | N>S | No | EVA | |
| rs1059821018 | 215 | P>L | No | EVA | |
| rs731277130 | 245 | V>G | No | EVA | |
| rs734289780 | 250 | H>P | No | EVA | |
| rs734964774 | 390 | S>P | No | EVA | |
| rs741151713 | 393 | T>N | No | EVA | |
| rs733008186 | 530 | N>H | No | EVA | |
| rs736477575 | 530 | N>T | No | EVA | |
| rs734324136 | 537 | D>A | No | EVA | |
| rs740123563 | 597 | S>P | No | EVA | |
| rs738129587 | 599 | K>E | No | EVA | |
| rs732170049 | 606 | R>G | No | EVA | |
| rs741102621 | 608 | T>A | No | EVA | |
| rs734844375 | 620 | H>R | No | EVA | |
| rs3385507164 | 621 | E>D | No | EVA | |
| rs3387664372 | 625 | S>N | No | EVA |
No associated diseases with A0A3S5ZPR1
No regional properties for A0A3S5ZPR1
| Type | Name | Position | InterPro Accession |
|---|---|---|---|
| No domain, repeats, and functional sites for A0A3S5ZPR1 | |||
3 GO annotations of cellular component
| Name | Definition |
|---|---|
| guanyl-nucleotide exchange factor complex | A protein complex that stimulates the exchange of guanyl nucleotides associated with a GTPase. |
| perinuclear region of cytoplasm | Cytoplasm situated near, or occurring around, the nucleus. |
| plasma membrane | The membrane surrounding a cell that separates the cell from its external environment. It consists of a phospholipid bilayer and associated proteins. |
5 GO annotations of molecular function
| Name | Definition |
|---|---|
| calcium ion binding | Binding to a calcium ion (Ca2+). |
| GTPase activator activity | Binds to and increases the activity of a GTPase, an enzyme that catalyzes the hydrolysis of GTP. |
| 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. |
| kinase binding | Binding to a kinase, any enzyme that catalyzes the transfer of a phosphate group. |
| small GTPase binding | Binding to a small monomeric GTPase. |
2 GO annotations of biological process
| Name | Definition |
|---|---|
| positive regulation of GTPase activity | Any process that activates or increases the activity of a GTPase. |
| 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. |
24 homologous proteins in AiPD
| UniProt AC | Gene Name | Protein Name | Species | Evidence Code |
|---|---|---|---|---|
| A6N9I4 | RASGRP2 | RAS guanyl-releasing protein 2 | Bos taurus (Bovine) | SS |
| Q1LZ97 | RASGRP4 | RAS guanyl-releasing protein 4 | Bos taurus (Bovine) | SS |
| P26675 | Sos | Protein son of sevenless | Drosophila melanogaster (Fruit fly) | SS |
| Q07890 | SOS2 | Son of sevenless homolog 2 | Homo sapiens (Human) | SS |
| Q5JS13 | RALGPS1 | Ras-specific guanine nucleotide-releasing factor RalGPS1 | Homo sapiens (Human) | PR |
| Q86X27 | RALGPS2 | Ras-specific guanine nucleotide-releasing factor RalGPS2 | Homo sapiens (Human) | PR |
| Q13905 | RAPGEF1 | Rap guanine nucleotide exchange factor 1 | Homo sapiens (Human) | PR |
| Q07889 | SOS1 | Son of sevenless homolog 1 | Homo sapiens (Human) | EV |
| Q8TDF6 | RASGRP4 | RAS guanyl-releasing protein 4 | Homo sapiens (Human) | SS |
| O95267 | RASGRP1 | RAS guanyl-releasing protein 1 | Homo sapiens (Human) | EV |
| Q7LDG7 | RASGRP2 | RAS guanyl-releasing protein 2 | Homo sapiens (Human) | EV SS |
| Q8IV61 | RASGRP3 | Ras guanyl-releasing protein 3 | Homo sapiens (Human) | SS |
| Q62245 | Sos1 | Son of sevenless homolog 1 | Mus musculus (Mouse) | SS |
| A2AR50 | Ralgps1 | Ras-specific guanine nucleotide-releasing factor RalGPS1 | Mus musculus (Mouse) | PR |
| Q8BTM9 | Rasgrp4 | RAS guanyl-releasing protein 4 | Mus musculus (Mouse) | SS |
| Q9ERD6 | Ralgps2 | Ras-specific guanine nucleotide-releasing factor RalGPS2 | Mus musculus (Mouse) | PR |
| Q02384 | Sos2 | Son of sevenless homolog 2 | Mus musculus (Mouse) | SS |
| Q9QUG9 | Rasgrp2 | RAS guanyl-releasing protein 2 | Mus musculus (Mouse) | SS |
| Q9Z1S3 | Rasgrp1 | RAS guanyl-releasing protein 1 | Mus musculus (Mouse) | SS |
| P0C643 | Rasgrp2 | RAS guanyl-releasing protein 2 | Rattus norvegicus (Rat) | SS |
| Q8R5I4 | Rasgrp4 | RAS guanyl-releasing protein 4 | Rattus norvegicus (Rat) | SS |
| Q9R1K8 | Rasgrp1 | RAS guanyl-releasing protein 1 | Rattus norvegicus (Rat) | SS |
| Q9N5D3 | sos-1 | Son of sevenless homolog | Caenorhabditis elegans | EV |
| A4IJ06 | rasgrp1 | RAS guanyl-releasing protein 1 | Xenopus tropicalis (Western clawed frog) (Silurana tropicalis) | SS |
| 10 | 20 | 30 | 40 | 50 | 60 |
| MGSNTLGKAA | TLDELLNTCI | EMFDDGENQC | SSHLPRIFLL | MHRWYLPSTE | LAVKLLNTYR |
| 70 | 80 | 90 | 100 | 110 | 120 |
| DASGENCNEF | RLKICYFMRY | WILEFPAEFN | LDLGLIRLTE | EFRELASQLG | YEDHIDLIDI |
| 130 | 140 | 150 | 160 | 170 | 180 |
| SSIPSYDWMR | RVTQRKKISK | KGKACLLFDH | LEPIELAEHL | TFLEHKSFRR | ISFTDYQSYV |
| 190 | 200 | 210 | 220 | 230 | 240 |
| IHGCLENNPT | LERSIALFNG | ISKWVQLMVL | SKPTPLQRAE | VITKFINVAQ | KLLHLQNFNT |
| 250 | 260 | 270 | 280 | 290 | 300 |
| LMAVVGGLSH | SSISRLKETH | SHLSSEVTKD | WNEMTELVSS | NGNYCNYRKA | FADCVGFKIP |
| 310 | 320 | 330 | 340 | 350 | 360 |
| ILGVHLKDLI | AVHVIFPDWI | DENKVNIVKM | QQLSITLNEL | VSLQTASHHL | EPNMDLINLL |
| 370 | 380 | 390 | 400 | 410 | 420 |
| TLSLDLYHTE | DDIYKLSLVL | EPRNSKSPTS | PTTPSKPVVP | LEWASGVVPK | PDPTVINKHI |
| 430 | 440 | 450 | 460 | 470 | 480 |
| RKLVDSVFRN | YDHDHDGYIS | QEDFESIAAN | FPFLDSFCVL | DKDQDGLISK | EEMMAYFLRA |
| 490 | 500 | 510 | 520 | 530 | 540 |
| KSQFQCKMGP | GFIHNFQEMT | YLKPTFCEHC | AGFLWGIIKQ | GYKCKDCGAN | CHKQCRDLLV |
| 550 | 560 | 570 | 580 | 590 | 600 |
| LACRKFSRGT | SVGSNHGSLP | SSPSLPPAQD | EVFEFPSVDA | EHQDLDGRAI | TLVTGSSRKI |
| 610 | 620 | 630 | 640 | 650 | 660 |
| SVRLQRATAS | QATQTEPLWH | EPGWSDSGSH | TFPKMKSKFH | GKAGKNKGFA | KWENEKPSMQ |
| 670 | 680 | 690 | |||
| ADVGIDAEAP | QHILEHNGIE | TLPERQESED | S |