The Eukaryotic Linear Motif resource for
Functional Sites in Proteins
Accession:
Functional site class:
G3BP binding motif
Functional site description:
The Ras GTPase activating protein SH3 Domain Binding Proteins (G3BPs) are RNA-binding proteins involved in the formation of RNA stress granules (SG) in response to environmental stress and viral infections. A number of cellular proteins associated with SG assembly are shown to interact with G3BP and additionally G3BP represents a target for many viruses which have evolved mechanisms to counteract the induction of SGs. G3BP is a modular protein and contains the RNA-binding RRM domain as well as protein/protein interaction domains which are together implicated in the dimerization of G3BP. The N-terminal NTF2-like domain is the most conserved part of the G3BP sequence and is required for the formation of SGs. The canonical FGDF peptide sequence was recently identified as a G3BP binding motif that mediates binding of proteins to the NTF2-like domain of G3BP.
ELM Description:
The canonical short linear motif FGDF is able to bind to the protein G3BP, which possesses a key role in stress granule formation. Molecular modeling (Panas,2015) and co-crystallization (Kristensen,2015) of G3BP with a synthetic peptide containing the sequence motif [FYLIMV].FG[DES]F revealed the binding into a hydrophobic cleft located in the NTF2-like domain of G3BP (4FCJ). The three conserved residues are essential for binding so that FGxF is considered as the core-binding motif. The glycine confers conformational flexibility, which is crucial for the positioning of the two phenylalanines in the binding pocket. The third residue of the core motif can be D, E or S, with a strong preference for aspartic acid in this position. The side chain of the third residue forms no hydrogen bonds or salt bridges with the binding domain. A hydrophobic amino acid placed upstream of the core-binding motif further ensures the adequate positioning of the core-binding motif in the binding pocket. All verified instances except the second consecutive motif in the chikungunya virus have at least two acidic residues within the downstream five positions. However, different modes of G3BP/FGDF binding are suggested. The molecular model of Panas et al. (Panas,2015) locates the two conserved phenylalanines in two hydrophobic pockets, which are created around the G3BP residues F15/F33 and L10/ V11, respectively. The crystal structure determination of G3BP/FGDF (5DRV) shows a different binding model. The FGDF peptide binds in the opposite direction by what the first phenylalanine contacts the hydrophobic sub-site near F15/F33 and the second phenylalanine is located in another hydrophobic sub-site around G3BP residues L22/F33.
Pattern: [FYLIMV].FG[DES]F
Pattern Probability: 0.0000012
Present in taxons: Alphavirus Bilateria Simplexvirus Viruses
Interaction Domain:
NTF2 (PF02136) Nuclear transport factor 2 (NTF2) domain (Stochiometry: 1 : 1)
o See 9 Instances for LIG_G3BP_FGDF_1
o Abstract
G3BP is a multifunctional protein, which is involved in stress granule assembly (SG), RNA metabolism and Ras signaling. There are three human isoforms of G3BP: G3BP1, G3BP2a and G3BP2b (117465269). They differ mainly by the number of SH3-binding PxxP motifs in the central region of the respective G3BP sequence. However both, G3BP1 and G3BP2, possess a well-described role in the formation of cytoplasmic RNA SGs (23279204).
The main function of SGs is the temporary storage of mRNA in response to stress caused by environmental factors and viral infections. SG assembly allows the repair and removal of stress-induced alterations as polysomes get disrupted and hence translation initiation is compromised. G3BP has a central role in the formation of SGs proved by the fact that an overexpression of G3BP is sufficient to induce SG, whereas a G3BP knockdown limits SG assembly (12642610).
The G3BP protein can be divided into five regions: the NTF2-like domain (PF02136), the acidic region, the PxxP motif, and two C-terminal RNA-binding modules (an RNA Recognition domain SM00360) and an arginine-glycine rich box (RGG), respectively). The NTF2-like domain and one RNA-binding motif are sufficient for G3BP multimerization involved in SG formation (12642610).
The N-terminal NTF2-like domain is the most conserved part of the G3BP sequence and has derived its name because of the resemblance to the nuclear transport factor 2. The crystal structure of the G3BP NTF2-like domain shows a homodimer with each chain comprised of a beta-sheet and three alpha helices (4FCJ, 24324649). The NTF2-like domain contains a hydrophobic binding groove for proteins with the canonical sequence motif FGDF, which is located in the vicinity of αI and αII (5RDV, Kristensen,2015). This hydrophobic cleft is further implicated in the nuclear shuttling activity of G3BP as this binding pocket also binds nucleoporins containing FxFG repeats (24324649). The interaction of FGDF-motif containing peptides with the hydrophobic groove on the surface of the G3BP NTF2-like domain has an affinity of 7μM and is 16-fold stronger than the binding of FxFG nucleoporin repeats (Kd = 115+/-3 μM).
Functionally diverse proteins share the FGDF motif and all serve as inhibitors of SG formation. The ubiquitin-specific protease 10 (USP-10) displays a conserved FGDF motif at residues 10-13 whereby G3BP serves as well as a regulator of the de-ubiquitinating activity of USP-10 (Soncini,2001).
The regulation of SG assembly is also considered as an antiviral host defense. Many viruses have developed mechanisms in order to block the formation of SG. The FGDF motif containing non-structural protein 3 (nsP3) of the human pathogenic Old World alphaviruses is shown to directly bind the G3BP-NTF2-like domain and hence sequestrate G3BP into cytoplasmic viral foci (Panas,2015).
o 6 selected references:

o 9 GO-Terms:

o 9 Instances for LIG_G3BP_FGDF_1
(click table headers for sorting; Notes column: =Number of Switches, =Number of Interactions)
Acc., Gene-, NameStartEndSubsequenceLogic#Ev.OrganismNotes
P36384 DBP
DNBI_HHV2
1142 1147 LGAAGEVFNFGDFGDADDHA TP 2 Human herpesvirus 2
1 
P04296 DBP
DNBI_HHV11
1142 1147 LGNAGEVFNFGDFGCEDDNA TP 4 Herpes simplex virus (type 1 / strain 17)
1 
P03317 Non-structural polyprotein
POLN_SINDV
1858 1863 RVTESEPVLFGSFEPGEVNS TP 8 Sindbis virus
3 
P03317 Non-structural polyprotein
POLN_SINDV
1835 1840 TGPTDVPMSFGSFSDGEIDE TP 8 Sindbis virus
3 
Q5XXP4 Non-structural polyprotein
POLN_CHIK3
1828 1833 ESLSSELLTFGDFSPGEVDD TP 12 Chikungunya virus strain Senegal 37997
3 
Q5XXP4 Non-structural polyprotein
POLN_CHIK3
1810 1815 APNETFPITFGDFDEGEIES TP 12 Chikungunya virus strain Senegal 37997
3 
P08411 Non-structural polyprotein
POLN_SFV
1802 1807 VDALASGITFGDFDDVLRLG TP 15 Semliki forest virus
2 
P08411 Non-structural polyprotein
POLN_SFV
1785 1790 AFRNKLPLTFGDFDEHEVDA TP 15 Semliki forest virus
2 
Q14694 USP10
UBP10_HUMAN
8 13 MALHSPQYIFGDFSPDEFNQ TP 9 Homo sapiens (Human)
2 
Please cite: ELM 2016-data update and new functionality of the eukaryotic linear motif resource. (PMID:26615199)

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