G3BP1

Summary

G3BP1 (G3BP stress granule assembly factor 1, HGNC:30292) is a protein-coding gene on chromosome 5q33.1, encoding Ras GTPase-activating protein-binding protein 1 (Q13283). Protein involved in various processes, such as stress granule formation and innate immunity.

This gene encodes one of the DNA-unwinding enzymes which prefers partially unwound 3’-tailed substrates and can also unwind partial RNA/DNA and RNA/RNA duplexes in an ATP-dependent fashion. This enzyme is a member of the heterogeneous nuclear RNA-binding proteins and is also an element of the Ras signal transduction pathway. It binds specifically to the Ras-GTPase-activating protein by associating with its SH3 domain. Several alternatively spliced transcript variants of this gene have been described, but the full-length nature of some of these variants has not been determined.

Source: NCBI Gene 10146 — RefSeq curated summary.

At a glance

• GWAS associations: 3
• Clinical variants (ClinVar): 84 total — 1 likely-pathogenic
• Druggable target: yes
• MANE Select transcript: NM_005754

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:30292
Approved symbol	G3BP1
Name	G3BP stress granule assembly factor 1
Location	5q33.1
Locus type	gene with protein product
Status	Approved
Aliases	HDH-VIII, G3BP
Ensembl gene	ENSG00000145907
Ensembl biotype	protein_coding
OMIM	608431
Entrez	10146

Gene structure

Transcript identifiers

Ensembl transcripts: 88 — 44 protein_coding, 22 nonsense_mediated_decay, 11 protein_coding_CDS_not_defined, 11 retained_intron

ENST00000356245, ENST00000394123, ENST00000507878, ENST00000517947, ENST00000518726, ENST00000519832, ENST00000520006, ENST00000520177, ENST00000520578, ENST00000522367, ENST00000522666, ENST00000522761, ENST00000523519, ENST00000627077, ENST00000676507, ENST00000676590, ENST00000676634, ENST00000676644, ENST00000676715, ENST00000676734, ENST00000676813, ENST00000676827, ENST00000676878, ENST00000676894, ENST00000676899, ENST00000676911, ENST00000676978, ENST00000677105, ENST00000677126, ENST00000677146, ENST00000677211, ENST00000677241, ENST00000677252, ENST00000677284, ENST00000677323, ENST00000677369, ENST00000677381, ENST00000677408, ENST00000677433, ENST00000677493, ENST00000677602, ENST00000677608, ENST00000677658, ENST00000677687, ENST00000677757, ENST00000677854, ENST00000677909, ENST00000677923, ENST00000678027, ENST00000678070, ENST00000678086, ENST00000678101, ENST00000678153, ENST00000678194, ENST00000678209, ENST00000678295, ENST00000678369, ENST00000678372, ENST00000678500, ENST00000678564, ENST00000678612, ENST00000678646, ENST00000678657, ENST00000678726, ENST00000678750, ENST00000678825, ENST00000678854, ENST00000678904, ENST00000678910, ENST00000678925, ENST00000678964, ENST00000678976, ENST00000679004, ENST00000679057, ENST00000679135, ENST00000679193, ENST00000679207, ENST00000679289, ENST00000871486, ENST00000871487, ENST00000871488, ENST00000871489, ENST00000871490, ENST00000937617, ENST00000937618, ENST00000937619, ENST00000958238, ENST00000958240

RefSeq mRNA: 2 — MANE Select: NM_005754 NM_005754, NM_198395

CCDS: CCDS4319

Canonical transcript exons

ENST00000356245 — 12 exons

Exon	Start	End
ENSE00001886878	151803885	151812785
ENSE00002139675	151771954	151772036
ENSE00003462263	151800218	151800346
ENSE00003478154	151794159	151794249
ENSE00003480665	151786572	151786715
ENSE00003500209	151799889	151800000
ENSE00003530893	151790889	151791062
ENSE00003574665	151800760	151800869
ENSE00003577419	151790323	151790404
ENSE00003584858	151797227	151797428
ENSE00003663932	151795479	151795575
ENSE00003677770	151799212	151799313

Expression profiles

Bgee: expression breadth ubiquitous, 295 present calls, max score 99.34.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 134.4576 / max 1594.0889, expressed in 1825 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
59675	124.8213	1825
59674	7.7366	1745
59679	0.9088	566
59677	0.5098	232
59676	0.4811	249

Top tissues by expression

295 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
ventricular zone	UBERON:0003053	99.34	gold quality
colonic epithelium	UBERON:0000397	99.12	gold quality
ganglionic eminence	UBERON:0004023	98.99	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	98.58	gold quality
islet of Langerhans	UBERON:0000006	98.56	gold quality
adrenal tissue	UBERON:0018303	98.55	gold quality
embryo	UBERON:0000922	98.51	gold quality
stromal cell of endometrium	CL:0002255	98.25	gold quality
calcaneal tendon	UBERON:0003701	98.11	gold quality
tonsil	UBERON:0002372	97.95	gold quality
hindlimb stylopod muscle	UBERON:0004252	97.92	gold quality
muscle of leg	UBERON:0001383	97.86	gold quality
gastrocnemius	UBERON:0001388	97.86	gold quality
rectum	UBERON:0001052	97.75	gold quality
lymph node	UBERON:0000029	97.74	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	97.71	gold quality
pericardium	UBERON:0002407	97.66	gold quality
gall bladder	UBERON:0002110	97.63	gold quality
tendon	UBERON:0000043	97.55	gold quality
endometrium	UBERON:0001295	97.43	gold quality
vermiform appendix	UBERON:0001154	97.38	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	97.35	gold quality
superior surface of tongue	UBERON:0007371	97.25	gold quality
cortical plate	UBERON:0005343	97.22	gold quality
right testis	UBERON:0004534	97.18	gold quality
muscle organ	UBERON:0001630	97.16	gold quality
caecum	UBERON:0001153	97.13	gold quality
biceps brachii	UBERON:0001507	97.09	gold quality
ovary	UBERON:0000992	97.05	gold quality
esophagus mucosa	UBERON:0002469	97.05	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-GEOD-81608	no	15.87
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

161 targeting G3BP1, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-518D-5P	100.00	67.51	979
HSA-MIR-518E-5P	100.00	67.66	954
HSA-MIR-518F-5P	100.00	67.51	979
HSA-MIR-519A-5P	100.00	67.66	954
HSA-MIR-519B-5P	100.00	67.66	954
HSA-MIR-519C-5P	100.00	67.66	954
HSA-MIR-520C-5P	100.00	67.51	979
HSA-MIR-522-5P	100.00	67.66	954
HSA-MIR-523-5P	100.00	67.66	954
HSA-MIR-526A-5P	100.00	67.51	979
HSA-MIR-8485	100.00	77.57	4731
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-450A-1-3P	100.00	69.33	1837
HSA-MIR-223-3P	99.99	70.14	1140
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-3692-3P	99.98	70.27	2139
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-2110	99.96	66.68	1930

Literature-anchored findings (GeneRIF, showing 40)

• involvement of cellular protein G3BP in transcription of intermediate stage genes may regulate the transition between early and late phases of vaccinia virus replication (PMID:15471883)
• G3BPs are scaffolding proteins linking signal transduction to RNA metabolism (review) (PMID:15602692)
• Hepatitis C virus viral gene and proteins may regulate the presence of host cellular proteins in detergent resistant membrane (PMID:16996479)
• Caprin-1/G3BP-1 complex is likely to regulate the transport and translation of mRNAs of proteins involved with synaptic plasticity in neurons (PMID:17210633)
• The expressions of G3BP and OPN proteins have a close relationship with lymphoid metastasis and survival in esophageal squamous carcinoma patients. (PMID:17253181)
• Both G3BP1 and G3BP2 isoforms may act as negative regulators of tumor suppressor protein p53. (PMID:17297477)
• The expression of G3BP and RhoC protein is closely related to the lymph node metastasis and survival in esophageal squamous carcinoma (ESC) patients. G3BP and RhoC proteins can be considered as predictors of prognosis in ESC patients. (PMID:17696235)
• Results illustrated a role for MK-STYX in regulating the ability of G3BP1 to integrate changes in growth-factor stimulation and environmental stress with the regulation of protein synthesis. (PMID:20180778)
• these results strongly indicate that (-)-epigallocatechin gallate suppresses lung tumorigenesis through its binding with G3BP1 (PMID:20424128)
• The kinetics of assembly of stress granules(SGs) in living cells demonstrated that Tudor-SN co-localizes with G3BP and is recruited to the same SGs in response to different stress stimuli. (PMID:20643132)
• Molecular and functional studies indicate that the interaction of G3BP1 with beta-F1 mRNA inhibits its translation at the initiation level, supporting a role for G3BP1 in the glycolytic switch that occurs in cancer. (PMID:20663914)
• The nuclear transport factor 2-like (NTF2-like) domain of human G3BP1 was subcloned, overexpressed in Escherichia coli and purified. (PMID:21206022)
• TAR DNA-binding protein 43 (TDP-43) regulates stress granule dynamics via differential regulation of G3BP and TIA-1. (PMID:21257637)
• CD24 may play a role in the inhibition of cell invasion and metastasis, and that intracellular CD24 inhibits invasiveness and metastasis through its influence on the posttranscriptional regulation of BART mRNA levels via G3BP RNase activity. (PMID:21266361)
• interaction between IncA and G3BP1 of Hep-2 cells infected with Chlamydophila psittaci reduces c-Myc concentration (PMID:21304914)
• overexpression of the amino (N)-terminal region of G3BP, including the binding region for BART mRNA, dominant-negatively inhibits formation of the complex between endogenous G3BP and BART mRNA, and increases the expression of BART. (PMID:21665939)
• arguments against G3BP1 being a genuine RasGAP-binding partner (PMID:22205990)
• In this report, we demonstrate that a novel peptide GAP161 blocked the functions of G3BP and markedly suppressed HCT116 cell growth through the induction of apoptosis (PMID:22703643)
• These findings establish a novel function for Poly(ADP-ribose) in the formation of G3BP-induced stress granules upon genotoxic stress. (PMID:22767504)
• Data indicate that assembly of large RasGAP SH3-binding protein (G3BP)-induced stress granules precedes phosphorylation of eukaryotic initiation factor 2alpha (eIF2alpha). (PMID:22833567)
• Data show that the nsP3/G3BP interaction also blocks stress granules (SGs) induced by other stresses than virus infection. (PMID:23087212)
• MK-STYX inhibits stress granule formation independently of G3BP-1 phosphorylation at Ser149. (PMID:23163895)
• both G3BP1 and G3BP2 play a role in the formation of SGs in various human cells and thereby recovery from these cellular stresses. (PMID:23279204)
• Data revealed that knockdown of G3BP inhibited the migration and invasion of human lung carcinoma cells through the inhibition of Src, FAK, ERK and NF-kappaB and decreased levels of MMP-2, MMP-9 and uPA. (PMID:24157923)
• G3BP1 regulation of cell proliferation in breast cancer cells, may occur via a regulatory effect on PMP22 expression. (PMID:24321297)
• Binding motifs specificity has been determined for human G3BP1 NTF2-like domain. (PMID:24324649)
• G3BP1, G3BP2 and CAPRIN1 are required for translation of interferon stimulated mRNAs and are targeted by a dengue virus non-coding RNA. (PMID:24992036)
• These findings disclose a novel mechanism of resveratrol-induced p53 activation and resveratrol-induced apoptosis by direct targeting of G3BP1. (PMID:24998844)
• G3BP1 has a role in modulating stress granule assembly during HIV-1 infection (PMID:25229650)
• Authors show that the PXXP domain within G3BP1 is essential for the recruitment of PKR to stress granules, for eIF2alpha phosphorylation driven by PKR, and for nucleating stress granules of normal composition. (PMID:25520508)
• eQTLs acting across multiple tissues are significant carriers of inherited risk for CAD. FLYWCH1, PSORSIC3, and G3BP1 are novel master regulatory genes in CAD that may be suitable targets. (PMID:25578447)
• Stress granule components G3BP1 and G3BP2 play a proviral role early in Chikungunya virus replication. (PMID:25653451)
• ICP8 binding to G3BP also inhibits SG formation, which is a novel function of HSV ICP8. (PMID:25658430)
• The G3BP1-Caprin1-PKR complex represents a new mode of PKR activation and is important for antiviral activity of G3BP1 and PKR during infection with mengovirus. (PMID:25784705)
• these findings demonstrate a critical role for YB-1 in stress granule formation through translational activation of G3BP1, and highlight novel functions for stress granules in tumor progression. (PMID:25800057)
• Our data define G3BP1 as a novel independent prognostic factor that is correlated with gastric cancer progression. (PMID:25809930)
• G3BP1 is essential for normal stress granule-processing body interactions and stress granule function. (PMID:25847539)
• Our findings identified a novel function of G3BP1 in the progression of breast cancer via activation of the epithelial-to-mesenchymal transition (PMID:25962958)
• G3BP1 granules were assembled independently of TIA-1 and had a negative impact on Dengue virus replication. (PMID:26350772)
• Host G3BP1 captures HIV-1 RNA transcripts and thereby restricts mRNA translation, viral protein production and virus particle formation. (PMID:26432022)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	g3bp1	ENSDARG00000017741
mus_musculus	G3bp1	ENSMUSG00000018583
rattus_norvegicus	G3bp1	ENSRNOG00000013186
drosophila_melanogaster	rin	FBGN0015778
caenorhabditis_elegans		WBGENE00010677

Paralogs (1): G3BP2 (ENSG00000138757)

Protein

Protein identifiers

Ras GTPase-activating protein-binding protein 1 — Q13283 (reviewed: Q13283)

Alternative names: ATP-dependent DNA helicase VIII, GAP SH3 domain-binding protein 1

All UniProt accessions (36): A0A7I2V274, A0A7I2V2S5, A0A7I2V2V1, A0A7I2V2X7, A0A7I2V326, A0A7I2V3C4, A0A7I2V3V2, A0A7I2V3Y4, A0A7I2V494, A0A7I2V496, A0A7I2V4D8, A0A7I2V4Y8, A0A7I2V533, Q13283, A0A7I2V548, A0A7I2V565, A0A7I2V5H1, A0A7I2V5M7, A0A7I2V651, A0A7I2YQB1, A0A7I2YQC2, A0A7I2YQF2, A0A7I2YQH0, A0A7I2YQM1, A0A7I2YQN9, A0A7I2YQP3, A0A7I2YQQ8, A0A7I2YQR4, A0A7I2YQU8, A0A7P0P2U7, E5RH00, E5RH42, E5RI46, E5RIF8, E5RJU8, Q5U0Q1

UniProt curated annotations — full annotation on UniProt →

Function. Protein involved in various processes, such as stress granule formation and innate immunity. Plays an essential role in stress granule formation. Stress granules are membraneless compartments that store mRNAs and proteins, such as stalled translation pre-initiation complexes, in response to stress. Promotes formation of stress granules phase-separated membraneless compartment by undergoing liquid-liquid phase separation (LLPS) upon unfolded RNA-binding: functions as a molecular switch that triggers RNA-dependent LLPS in response to a rise in intracellular free RNA concentrations. Also acts as an ATP- and magnesium-dependent helicase: unwinds DNA/DNA, RNA/DNA, and RNA/RNA substrates with comparable efficiency. Acts unidirectionally by moving in the 5’ to 3’ direction along the bound single-stranded DNA. Unwinds preferentially partial DNA and RNA duplexes having a 17 bp annealed portion and either a hanging 3’ tail or hanging tails at both 5’- and 3’-ends. Plays an essential role in innate immunity by promoting CGAS and RIGI activity. Participates in the DNA-triggered cGAS/STING pathway by promoting the DNA binding and activation of CGAS. Triggers the condensation of cGAS, a process probably linked to the formation of membrane-less organelles. Also enhances RIGI-induced type I interferon production probably by helping RIGI at sensing pathogenic RNA. May also act as a phosphorylation-dependent sequence-specific endoribonuclease in vitro: Cleaves exclusively between cytosine and adenine and cleaves MYC mRNA preferentially at the 3’-UTR.

Subunit / interactions. Homodimer and oligomer. Component of a TAU mRNP complex, at least composed of IGF2BP1, ELAVL4 and G3BP1. Binds to the SH3 domain of Ras GTPase-activating protein (RASA1) in proliferating cells. No interaction in quiescent cells. Interacts (via NTF2 domain) with USP10; inhibiting stress granule formation by lowering G3BP1 valence. Interacts (via NTF2 domain) with CAPRIN1; promoting stress granule formation by lowering the saturation-concentration of G3BP1. Interacts (via NTF2 domain) with UBAP2L; promoting stress granule formation. Associates (via RG-rich region) with 40S ribosome subunits. Interacts with RPTOR and SPAG5; this complex is increased by oxidative stress. Interacts with ATXN2L. Interacts with STYXL1. Interacts with CGAS (via N-terminus); this interaction promotes the DNA-binding and activation of CGAS. Interacts (via C-terminus) with RIGI. Interacts with PABPC1. Interacts with QKI (isoforms QKI6 and QKI7); directing N(7)-methylguanine-containing mRNAs to stress granules. (Microbial infection) Interacts with Semliki forest virus non-structural protein 3 (via C-terminus); this interaction inhibits the formation of stress granules on viral mRNAs and the nsp3-G3BP1 complexes bind viral RNAs and probably orchestrate the assembly of viral replication complexes. (Microbial infection) Interacts with Chikungunya virus non-structural protein 3 (via C-terminus); this interaction inhibits the formation of stress granules on viral mRNAs and the nsp3-G3BP1 complexes bind viral RNAs and probably orchestrate the assembly of viral replication complexes. (Microbial infection) Interacts with Sindbis virus non-structural protein 3 (via C-terminus); this interaction inhibits the formation of stress granules on viral mRNAs and the nsp3-G3BP1 complexes bind viral RNAs and probably orchestrate the assembly of viral replication complexes. (Microbial infection) Interacts with Zika virus capsid protein C; this interaction is probably linked to the inhibition of stress granules formation by the virus. (Microbial infection) Interacts with reovirus type 2 protein sigma-NS; this interaction induces the relocalization of G3BP1 to the outer periphery of sigma-NS/mu-Ns viral factories and is probably involved in the suppression of the integrated stress response by the virus. (Microbial infection) Interacts with SARS-CoV-2 N protein; the interaction is enhanced by host HDAC6 which deacetylates the viral N protein and promotes N protein association with G3BP1, disrupting stress granule formation and facilitating viral replication. Interacts with HDAC6; the interaction increases during SARS-CoV-2 infection.

Subcellular location. Cytoplasm. Cytosol. Perikaryon. Stress granule. Nucleus.

Tissue specificity. Ubiquitous.

Post-translational modifications. Phosphorylation of the acidic disordered region regulates stress granule assembly. RASA1-dependent phosphorylation of Ser-149 induces a conformational change that prevents self-association. Dephosphorylation after HRAS activation is required for stress granule assembly. Ser-149 phosphorylation induces partial nuclear localization. Ubiquitinated by TRIM21 via ‘Lys-63’-linked polyubiquitination in the NTF2 domain in response to heat shock, leading to stress granule disassembly: ubiquitination promotes interaction with the FAF2 adapter, followed by interaction with VCP, which extracts G3BP1 from stress granules, leading to stress granule disassembly. In case of prolonged stress, ubiquitination by TRIM21 leads to autophagy-dependent degradation of G3BP1 via recruitment of ubiquitinated G3BP1 by SQSTM1 and/or CALCOCO2 to autophagosomes. (Microbial infection) Cleaved by human enterovirus 71; this cleavage induces the disassembly of cytoplasmic stress granules. Cleaved by Foot-and-mouth disease virus; this cleavage suppresses the formation of cytoplasmic stress granules. Arg-435 is dimethylated, probably to asymmetric dimethylarginine. (Microbial infection) Cleaved by Encephalomyocarditis virus protease 3C; this cleavage suppresses the formation of cytoplasmic stress granules.

Activity regulation. Under physiological conditions, G3BP1 adopts a compact state that is stabilized by intramolecular interactions between the RG-rich and the acidic regions that inhibit phase separation. Upon stress, polysomes disassemble and mRNAs are released in an unfolded protein-free state. Binding of unfolded mRNA to G3BP1 outcompetes the intramolecular interactions and RNA-bound G3BP1 adopts an expanded conformation in which the RG-rich region becomes exposed to engage in protein-protein and protein-RNA interactions, allowing physical cross-linking of RNA molecules to form protein-RNA condensates, leading to liquid-liquid phase separation (LLPS).

Cofactor. Mg(2+) is required for helicase activity.

Domain organisation. Can mediate both protein-protein and protein-RNA interactions via the NTF2 domain and RNA-binding domain RRM; protein-protein and protein-RNA interactions are essential for undergoing liquid-liquid phase separation (LLPS). The acidic disordered region acts as a negative regulator of phase separation. The NTF2 domain mediates interaction with CAPRIN1 and USP10 regulators, thereby regulating assembly of stress granules.

Isoforms (2)

UniProt ID	Names	Canonical?
Q13283-1	1	yes
Q13283-2	2

RefSeq proteins (2): NP_005745, NP_938405 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000504	RRM_dom	Domain
IPR002075	NTF2_dom	Domain
IPR012677	Nucleotide-bd_a/b_plait_sf	Homologous_superfamily
IPR018222	Nuclear_transport_factor_2_euk	Domain
IPR032710	NTF2-like_dom_sf	Homologous_superfamily
IPR034374	G3BP1_RRM	Domain
IPR035979	RBD_domain_sf	Homologous_superfamily
IPR039539	Ras_GTPase_bind_prot	Family

Pfam: PF00076, PF02136

Catalyzed reactions (Rhea), 1 shown:

• ATP + H2O = ADP + phosphate + H(+) (RHEA:13065)

UniProt features (83 total): mutagenesis site 19, modified residue 16, cross-link 11, strand 7, compositionally biased region 6, region of interest 6, helix 6, sequence variant 5, domain 2, splice variant 2, initiator methionine 1, chain 1, site 1

Structure

Experimental structures (PDB)

20 structures.

PDB	Method	Resolution (Å)
4FCJ	X-RAY DIFFRACTION	1.62
3Q90	X-RAY DIFFRACTION	1.7
8TH1	X-RAY DIFFRACTION	1.8
5FW5	X-RAY DIFFRACTION	1.92
6TA7	X-RAY DIFFRACTION	1.93
8TH6	X-RAY DIFFRACTION	2.34
7SUO	X-RAY DIFFRACTION	2.35
7S17	X-RAY DIFFRACTION	2.36
9CC6	X-RAY DIFFRACTION	2.4
7XHG	X-RAY DIFFRACTION	2.46
8TH5	X-RAY DIFFRACTION	2.62
9IVQ	ELECTRON MICROSCOPY	2.66
7XHF	X-RAY DIFFRACTION	2.68
8V1L	X-RAY DIFFRACTION	2.68
4FCM	X-RAY DIFFRACTION	2.69
9IVR	ELECTRON MICROSCOPY	2.8
9J5S	X-RAY DIFFRACTION	2.84
8TH7	X-RAY DIFFRACTION	2.88
9IVS	ELECTRON MICROSCOPY	2.97
4IIA	X-RAY DIFFRACTION	3.3

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q13283-F1	67.44	0.29

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (1): 325–326 (cleavage; by human enterovirus 71 protease 3c)

Post-translational modifications (27): 143, 149, 231, 232, 250, 253, 373, 376, 429, 435, 435, 435, 447, 460, 460, 465, 36, 50, 59, 64 …

Mutagenesis-validated functional residues (19):

Position	Phenotype
15	decreased interaction with usp10.
33	abolished interaction with caprin1 and ability to undergo liquid-liquid phase separation. abolished interaction with usp
36	in 10kr; abolished ubiquitination in response to heat shock, leading to decreased stress granule disassembly when associ
50	in 10kr; abolished ubiquitination in response to heat shock, leading to decreased stress granule disassembly when associ
59	in 10kr; abolished ubiquitination in response to heat shock, leading to decreased stress granule disassembly when associ
64	in 10kr; abolished ubiquitination in response to heat shock, leading to decreased stress granule disassembly when associ
76	in 10kr; abolished ubiquitination in response to heat shock, leading to decreased stress granule disassembly when associ
123	in 10kr; abolished ubiquitination in response to heat shock, leading to decreased stress granule disassembly when associ
124	does not affect interaction with usp10.
149	slightly increased ability to undergo liquid-liquid phase separation. increased ability to undergo liquid-liquid phase s
149	mimics phosphorylation; decreased ability to undergo liquid-liquid phase separation. cytoplasmic and nuclear; no assembl
232	slightly increased ability to undergo liquid-liquid phase separation; when associated with a-149. cytoplasmic. partially
232	cytoplasmic. partially nuclear; when associated with e-149.
325	loss of cleavage by human enterovirus 71 protease 3c.
353	in 10kr; abolished ubiquitination in response to heat shock, leading to decreased stress granule disassembly when associ
357	in 10kr; abolished ubiquitination in response to heat shock, leading to decreased stress granule disassembly when associ
376	in 10kr; abolished ubiquitination in response to heat shock, leading to decreased stress granule disassembly when associ
380–382	abolished mrna-binding and ability to undergo liquid-liquid phase separation.
393	in 10kr; abolished ubiquitination in response to heat shock, leading to decreased stress granule disassembly when associ

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-9705671	SARS-CoV-2 activates/modulates innate and adaptive immune responses

MSigDB gene sets: 325 (showing top): CREL_01, AP1_01, BORCZUK_MALIGNANT_MESOTHELIOMA_UP, GOMF_ENDONUCLEASE_ACTIVITY, MORF_SMC1L1, GOBP_POSITIVE_REGULATION_OF_TYPE_I_INTERFERON_PRODUCTION, XU_GH1_AUTOCRINE_TARGETS_UP, GOMF_NUCLEASE_ACTIVITY, MATTIOLI_MGUS_VS_PCL, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, MORF_RAD21, GOBP_POSITIVE_REGULATION_OF_CYTOKINE_PRODUCTION, MORF_HDAC2, GOBP_REGULATION_OF_WNT_SIGNALING_PATHWAY, MORF_PSMC2

GO Biological Process (8): Ras protein signal transduction (GO:0007265), positive regulation of type I interferon production (GO:0032481), stress granule assembly (GO:0034063), innate immune response (GO:0045087), defense response to virus (GO:0051607), negative regulation of canonical Wnt signaling pathway (GO:0090090), immune system process (GO:0002376), positive regulation of stress granule assembly (GO:0062029)

GO Molecular Function (17): DNA binding (GO:0003677), DNA helicase activity (GO:0003678), RNA binding (GO:0003723), RNA helicase activity (GO:0003724), mRNA binding (GO:0003729), endonuclease activity (GO:0004519), ATP binding (GO:0005524), ATP hydrolysis activity (GO:0016887), DNA/RNA helicase activity (GO:0033677), ribosomal small subunit binding (GO:0043024), molecular condensate scaffold activity (GO:0140693), nucleotide binding (GO:0000166), nucleic acid binding (GO:0003676), helicase activity (GO:0004386), nuclease activity (GO:0004518), protein binding (GO:0005515), hydrolase activity (GO:0016787)

GO Cellular Component (8): nucleus (GO:0005634), cytoplasm (GO:0005737), cytosol (GO:0005829), focal adhesion (GO:0005925), cytoplasmic stress granule (GO:0010494), perikaryon (GO:0043204), membrane (GO:0016020), cytoplasmic ribonucleoprotein granule (GO:0036464)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
SARS-CoV-2-host interactions	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
helicase activity	3
nucleic acid binding	2
ATP-dependent activity, acting on DNA	2
ATP-dependent activity, acting on RNA	2
catalytic activity, acting on RNA	2
ATP-dependent activity	2
binding	2
catalytic activity, acting on a nucleic acid	2
cytoplasm	2
small GTPase-mediated signal transduction	1
positive regulation of cytokine production	1
regulation of type I interferon production	1
type I interferon production	1
membraneless organelle assembly	1
immune response	1
defense response to symbiont	1
defense response	1
response to virus	1
negative regulation of Wnt signaling pathway	1
canonical Wnt signaling pathway	1
regulation of canonical Wnt signaling pathway	1
biological_process	1
stress granule assembly	1
regulation of stress granule assembly	1
positive regulation of organelle assembly	1
RNA binding	1
nuclease activity	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
ribonucleoside triphosphate phosphatase activity	1
ribosome binding	1
protein-macromolecule adaptor activity	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
nucleic acid conformation isomerase activity	1
catalytic activity	1
intracellular membrane-bounded organelle	1
intracellular anatomical structure	1
cell-substrate junction	1

Protein interactions and networks

STRING

3484 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
G3BP1	TIA1	P31483	997
G3BP1	TIAL1	Q01085	995
G3BP1	CAPRIN1	Q14444	994
G3BP1	RASA1	P20936	993
G3BP1	EIF4G1	Q04637	978
G3BP1	PABPC1	P11940	975
G3BP1	EIF3B	P55884	967
G3BP1	USP10	Q14694	965
G3BP1	TARDBP	Q13148	949
G3BP1	G3BP2	Q9UN86	898
G3BP1	SH3BP5	O60239	885
G3BP1	ELAVL1	Q15717	883
G3BP1	UPF1	Q92900	880
G3BP1	FXR1	P51114	872
G3BP1	EIF4A1	P04765	869

IntAct

395 interactions, top by confidence:

A	B	Type	Score
IKBKG	IKBKB	psi-mi:“MI:0914”(association)	0.980
G3BP1	N	psi-mi:“MI:0403”(colocalization)	0.980
N	G3BP1	psi-mi:“MI:0914”(association)	0.980
N	G3BP1	psi-mi:“MI:0407”(direct interaction)	0.980
N	G3BP1	psi-mi:“MI:0915”(physical association)	0.980
G3BP1	N	psi-mi:“MI:0915”(physical association)	0.980
G3BP1	N	psi-mi:“MI:0407”(direct interaction)	0.980
N	G3BP1	psi-mi:“MI:0403”(colocalization)	0.980

BioGRID (1282): G3BP1 (Affinity Capture-MS), G3BP1 (Affinity Capture-MS), G3BP1 (Affinity Capture-MS), G3BP1 (Affinity Capture-Western), G3BP1 (Affinity Capture-MS), G3BP1 (Affinity Capture-MS), G3BP1 (Affinity Capture-MS), G3BP1 (Affinity Capture-MS), G3BP1 (Affinity Capture-MS), G3BP1 (Affinity Capture-MS), ADD3 (Co-fractionation), ADSL (Co-fractionation), G3BP1 (Co-fractionation), G3BP1 (Co-fractionation), G3BP1 (Co-fractionation)

ESM2 similar proteins: A5D7P8, A6QLK2, F1LQ48, O55047, O95628, P25916, P35226, P59326, P97855, Q08CW1, Q0VCY1, Q0VCZ3, Q12906, Q13148, Q13283, Q1ECX4, Q32KX7, Q32LC7, Q3SWT1, Q3ZBD9, Q4R5D9, Q5FVP2, Q5PRC7, Q5R601, Q5R8L2, Q5RB87, Q5SDR3, Q5U2U0, Q5ZLN5, Q64213, Q66K94, Q6DE02, Q6NRF9, Q86UE8, Q8BGW5, Q8BT14, Q8C0V0, Q8R2Y9, Q90ZY6, Q91YT7

Diamond homologs: A0A0D1C8Z4, A0A0D1DZT6, A2RVS6, A5DM21, A5DW14, B5FXN8, F1QB54, F4HT49, F4I3B3, F4JHI7, G3V6S8, O08583, O13845, O22315, O35326, O59670, O74400, P04147, P19682, P19683, P19684, P20965, P49313, P49314, P78814, P82277, P97855, Q04836, Q08170, Q08935, Q08937, Q09167, Q13242, Q13243, Q13247, Q13283, Q14498, Q1ZXC2, Q28FB9, Q32LC7

SIGNOR signaling

13 interactions.

A	Effect	B	Mechanism
G3BP1	up-regulates	Stress_granules
CSNK2A1	“down-regulates activity”	G3BP1	phosphorylation
N	“down-regulates activity”	G3BP1	binding
G3BP1	“up-regulates activity”	EIF2AK2	binding
G3BP1	“up-regulates activity”	G3BP2	binding
G3BP2	“up-regulates activity”	G3BP1	binding
G3BP1	“down-regulates activity”	DDX58	binding
CAPRIN1	“up-regulates activity”	G3BP1	binding
G3BP1	“up-regulates quantity”	DDX58
PARP10	“up-regulates activity”	G3BP1	“post translational modification”
Viral_dsRNA	“up-regulates activity”	G3BP1	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 135 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
NOD1/2 Signaling Pathway	5	16.7×	3e-03
Regulation of TNFR1 signaling	5	11.8×	6e-03
Activation of NF-kappaB in B cells	5	10.4×	9e-03
PKR-mediated signaling	6	8.9×	6e-03

GO biological processes:

GO term	Partners	Fold	FDR
canonical NF-kappaB signal transduction	5	15.5×	4e-03
tumor necrosis factor-mediated signaling pathway	5	14.0×	5e-03
obsolete positive regulation of NF-kappaB transcription factor activity	7	12.2×	6e-04
negative regulation of translation	6	10.0×	5e-03
negative regulation of canonical NF-kappaB signal transduction	6	8.7×	7e-03
translation	9	7.8×	6e-04
positive regulation of canonical NF-kappaB signal transduction	11	6.8×	4e-04
chromatin remodeling	9	5.6×	5e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

84 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	1
Uncertain significance	66
Likely benign	0
Benign	0

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
3602241	NM_005754.3(G3BP1):c.95+1G>A	Likely pathogenic

SpliceAI

2197 predictions. Top by Δscore:

Variant	Effect	Δscore
5:151772412:C:A	donor_gain	1.0000
5:151786713:TAG:T	donor_gain	1.0000
5:151786714:AGGTA:A	donor_loss	1.0000
5:151786716:G:GG	donor_gain	1.0000
5:151786716:GT:G	donor_loss	1.0000
5:151786717:T:A	donor_loss	1.0000
5:151790401:GAAA:G	donor_gain	1.0000
5:151790402:A:T	donor_gain	1.0000
5:151790402:AAAG:A	donor_loss	1.0000
5:151790405:G:GG	donor_gain	1.0000
5:151790405:GTAAG:G	donor_loss	1.0000
5:151790406:TAAG:T	donor_loss	1.0000
5:151790886:A:AG	acceptor_gain	1.0000
5:151790886:AAG:A	acceptor_gain	1.0000
5:151790887:A:AG	acceptor_gain	1.0000
5:151790887:AG:A	acceptor_gain	1.0000
5:151790888:G:A	acceptor_gain	1.0000
5:151790888:G:GG	acceptor_gain	1.0000
5:151790888:GGA:G	acceptor_gain	1.0000
5:151790888:GGAA:G	acceptor_gain	1.0000
5:151791021:GCTT:G	donor_gain	1.0000
5:151791061:AGGTA:A	donor_loss	1.0000
5:151791063:GT:G	donor_loss	1.0000
5:151794245:GGAGG:G	donor_gain	1.0000
5:151794246:GAGGG:G	donor_gain	1.0000
5:151795473:A:AG	acceptor_gain	1.0000
5:151795474:C:G	acceptor_gain	1.0000
5:151795477:A:AG	acceptor_gain	1.0000
5:151795478:G:GC	acceptor_gain	1.0000
5:151795478:GA:G	acceptor_gain	1.0000

AlphaMissense

3057 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
5:151786652:T:A	V11D	1.000
5:151786654:G:A	G12R	1.000
5:151786654:G:C	G12R	1.000
5:151786654:G:T	G12W	1.000
5:151786655:G:A	G12E	1.000
5:151786655:G:T	G12V	1.000
5:151786660:G:A	E14K	1.000
5:151786663:T:A	F15I	1.000
5:151786663:T:C	F15L	1.000
5:151786663:T:G	F15V	1.000
5:151786664:T:C	F15S	1.000
5:151786664:T:G	F15C	1.000
5:151786665:T:A	F15L	1.000
5:151786665:T:G	F15L	1.000
5:151786666:G:A	V16M	1.000
5:151786667:T:A	V16E	1.000
5:151786670:G:C	R17T	1.000
5:151786670:G:T	R17I	1.000
5:151786671:A:C	R17S	1.000
5:151786671:A:T	R17S	1.000
5:151786673:A:C	Q18P	1.000
5:151786674:G:C	Q18H	1.000
5:151786674:G:T	Q18H	1.000
5:151786675:T:C	Y19H	1.000
5:151786675:T:G	Y19D	1.000
5:151786676:A:G	Y19C	1.000
5:151786678:T:C	Y20H	1.000
5:151786678:T:G	Y20D	1.000
5:151786685:T:C	L22P	1.000
5:151786688:T:C	L23P	1.000

dbSNP variants (sampled 300 via entrez): RS1000095940 (5:151789350 C>T), RS1000123448 (5:151780506 G>GT), RS1000158539 (5:151797334 A>T), RS1000279282 (5:151789139 A>T), RS1000397659 (5:151770452 A>G), RS1000493423 (5:151807422 T>A), RS1000508052 (5:151784975 GT>G), RS1000574350 (5:151779729 A>C,G), RS1000638908 (5:151790271 ATAAACT>A), RS1000691143 (5:151790677 AGT>A), RS1000787751 (5:151812292 G>C), RS1000798320 (5:151773228 G>T), RS1000844465 (5:151807181 T>C), RS1000850793 (5:151801114 T>A,C), RS1000933459 (5:151779421 C>G,T)

Disease associations

OMIM: gene MIM:608431 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST010726_28	Periventricular white matter hyperintensities	2.000000e-06
GCST90002401_25	Platelet distribution width	2.000000e-09
GCST90002404_218	Red cell distribution width	2.000000e-10

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0005665	white matter hyperintensity measurement
EFO:0007984	platelet component distribution width
EFO:0009188	Red cell distribution width

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6067419 (SINGLE PROTEIN)

PharmGKB: 1 entry (VIP=true, CPIC=false)

ChEMBL bioactivities

2 potent at pChembl≥5 of 2 total, top 2 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.06	Kd	87.01	nM	CHEMBL5653589
7.06	ED50	87.01	nM	CHEMBL5653589

PubChem BioAssay actives

1 with measured affinity, of 2 total; 1 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148407: Binding affinity to human G3BP1 incubated for 45 mins by Kinobead based pull down assay	kd	0.0870	uM

CTD chemical–gene interactions

76 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
bisphenol A	affects cotreatment, increases phosphorylation, decreases expression, increases expression	4
Valproic Acid	decreases expression	4
trichostatin A	affects cotreatment, decreases expression, increases expression	3
arsenite	affects cotreatment, increases phosphorylation, affects binding, decreases reaction, increases reaction (+4 more)	3
sodium arsenite	affects localization, decreases expression	3
perfluorooctanoic acid	decreases expression	2
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	decreases expression, affects cotreatment	2
Air Pollutants	affects cotreatment, decreases expression, increases abundance, affects expression	2
Formaldehyde	decreases expression, affects binding, affects reaction	2
Ozone	affects cotreatment, decreases expression, increases abundance, affects expression	2
Phenylmercuric Acetate	decreases expression, affects cotreatment	2
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression, increases expression	2
aristolochic acid I	decreases expression	1
FR900359	increases phosphorylation	1
geldanamycin	increases expression	1
syringic acid	affects localization, increases expression	1
urushiol	increases expression	1
triphenyl phosphate	affects expression	1
alpha-pinene	affects cotreatment, decreases expression, increases abundance	1
uranyl acetate	affects expression	1
pyrogallol 1,3-dimethyl ether	increases expression, affects cotreatment, decreases expression, affects localization	1
decabromobiphenyl ether	decreases expression	1
beta-lapachone	decreases expression	1
methacrylaldehyde	affects cotreatment, decreases expression, increases abundance	1
microcystin RR	increases expression	1
CGP 52608	increases reaction, affects binding	1
calfactant	increases expression, affects cotreatment	1
abrine	decreases expression	1
bromovanin	increases expression	1
dorsomorphin	affects cotreatment, decreases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5651449	Binding	Binding affinity to human G3BP1 incubated for 45 mins by Kinobead based pull down assay	NVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family. — ChemMedChem

Cellosaurus cell lines

2 cell lines: 2 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_B1C5	Abcam A-431 G3BP1 KO	Cancer cell line	Female
CVCL_D1SL	Abcam U-87MG G3BP1 KO	Cancer cell line	Male

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.