| Accession: | |
|---|---|
| Functional site class: | WAVE regulatory complex (WRC) binding site motif |
| Functional site description: | The WASP family verprolin homologous protein (WAVE) regulatory complex (WRC) regulates actin cytoskeletal dynamics at distinct membrane-proximal sites. Protocadherins, ROBOs, netrin receptors, neuroligins, GPCRs, and channels employ the WIRS motif to recruit the WRC to specific locations where it stimulates actin nucleation through modulating the Arp2/3 complex. The WIRS motif binds to a highly conserved composite interaction surface of the WRC formed by the Sra and Abi subunits, therefore the interaction requires the entire WRC complex to be assembled. |
| ELM Description: | Mutational screening of the protocadherin 10 cytoplasmic tail indicated a consensus of ϕx[TS]Fxx for the WRC-binding motif where the last two positions show some restrictions on allowed amino acids, though no consensus could be made (Chen,2014). In the structure of the WIRS binding surface (4N78) a selenomethionine replaces the original Phe in the +1 position and packs against E1084 and L1090 of Sra1 and Phe at +4 of the WIRS. The +1 residue is always a bulky hydrophobic and enters a deep hydrophobic pocket. The side chain in the +2 position faces the solvent, so it does not affect binding. The side chain of Thr at +3 forms an extended hydrogen bonding network with several residues in Sra1 and Abi2, and with the peptide bond amide group of the Thr itself: This H bond arrangement restricts the position to threonine and serine residues. The side chain of Phe in the +4 position inserts into another hydrophobic pocket, in this case lined by four residues of Sra1 and another four of Abi2 stacking against Y923 of Sra1 and making cation-pi interactions with R106 of Abi2. Phe appears to be fully required at this position. Many amino acids are allowed at +5 and +6 since these positions do not interact directly with the WRC surface. However, Gly at +5 adopts a left-handed α helical conformation to position Lys (+6) such that it can hydrogen bond with the backbone of the selenomethionine at position +1 in the WIRS motif. Other amino acids at position +5 would certainly adopt different conformations, and therefore hydrogen bonding between positions +1 and +6 may not be generally observed. Also, backbone H-bonding suggests that proline would likely be excluded in position +5, which is confirmed by the evolutionary conservation profiles of the known WIRS instances (Chen,2014). |
| Pattern: | [FYILMV].[TS]F(G|[^P]). |
| Pattern Probability: | 0.0005802 |
| Present in taxon: | Metazoa |
| Interaction Domains: |
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 Abstract |
The ability to dynamically rearrange the actin cytoskeleton according to functional needs is vital to eukaryotic cells. The conserved C-terminal VCA (Verprolin-homology, Central, Acidic) sequence of Wiskott-Aldrich Syndrome Proteins (WASPs) stimulates the actin-nucleating activity of the Arp2/3 complex, thereby regulating actin dynamics. The conserved WASP family verprolin homologous protein (WAVE) plays a pivotal role in numerous cellular processes, such as adhesion, migration, division, and fusion. WAVE is part of a conserved, 400 kDa protein complex called the WAVE regulatory complex (WRC) that is made up of five different subunits arranged into two subcomplexes: Sra1/Cyfip1 (or the ortholog PIR121/Cyfip2) and Nap1/Hem2/Kette (or the ortholog Hem1) make up one of the subcomplexes, while Abi2 (or the orthologs Abi1 and Abi3), HSPC300/ Brick1, and WAVE1/SCAR (or the orthologs WAVE2 and WAVE3) comprise the other (Eden,2002; Chen,2010). Through an autoinhibitory mechanism, the WRC complex can sequester the VCA and thereby down-regulate the Arp2/3 complex stimulatory activity of the WAVE subunit (Chen,2010). When the WRC is recruited to the membrane by its cognate partners, the internal inhibition of WAVE is relaxed through a series of cooperative events (Chen,2014). WRC partners follow different mechanisms to contact the complex. Among them, membrane proteins belonging to different families, such as protocadherins, ROBOs, netrin receptors, neuroligins, GPCRs, and channels typically recruit the WRC to specific membrane-proximal locations by a short linear motif termed WRC Interacting Receptor Sequence (WIRS) embedded in their disordered cytoplasmic tails. The WIRS motif binds to a highly conserved pocket on the WRC surface formed by the Sra and Abi subunits of the two different subcomplexes, therefore the interaction strictly requires the entire WRC complex to be preassembled (Chen,2014). The WRC-WIRS interaction is highly conserved in animals (Metazoa) and it is also present in Choanoflagellata that is the closest phylogenetic group to Metazoa among Opisthokonta (Chen,2014). WIRS/WRC interactions have been linked to inherited diseases. For example, seven cases of epilepsy and mental retardation in females (EFMR) were reported that most probably arose because of truncations of the cytoplasmic tail of PCDH19, all resulting in the loss of its WIRS motif (Dimova,2012). Also, partial truncation of the DCC cytoplasmic tail that removed its WIRS motif caused congenital mirror movement in four individuals (Depienne,2011). |
9 selected references:
8 GO-Terms:
22 Instances for LIG_WRC_WIRS_1
(click table headers for sorting; Notes column: =Number of Switches, =Number of Interactions)
Please cite:
ELM-the Eukaryotic Linear Motif resource-2024 update.
(PMID:37962385)
ELM data can be downloaded & distributed for non-commercial use according to the ELM Software License Agreement
ELM data can be downloaded & distributed for non-commercial use according to the ELM Software License Agreement