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|Functional site class:||Actin-binding motifs|
|Functional site description:||The function of actin in the cell is regulated in a variety of ways, including interactions with the RPEL motifs and WH2 motifs, which bind to actin's hydrophobic cleft formed by its subdomains 1 and 3.
RPEL motifs, unstructured in solution, form two helices linked by a loop upon binding. They are known to sequester MRTF transcription factors in the cytosol. RPEL-containing proteins have been found in metazoans, as well as in fungi.
WH2 motifs are present in many eukaryotic organisms, including metazoa, plants and fungi. The structure of the motif comprises a short N-terminal helix of a variable length followed by an irregular region. It acts via interactions with G-actin, thus promoting or inhibiting the filament assembly. In some proteins WH2 motifs are also involved in regulation of the filament nucleation process. The differences in the functioning of various WH2-containing proteins may result from motif variants, which in several cases are not fully consistent with the assumed conservation pattern.
|ELMs:||LIG_Actin_RPEL_3 LIG_Actin_WH2_1 LIG_Actin_WH2_2|
|Description:|| Although unstructured in solution, upon actin binding the RPEL motif forms an L- shaped structure comprising of two alpha-helices separated by a short linking loop.
The key amino acid in the motif is arginine, located at the end of the first helix (in position 8), which is invariant. Mutational analysis proved that this residue is fundamental for actin binding. It is usually followed by proline within the linker which due to its propensity to form turns influences the structural flexibility of the motif. Proline in position 1 is often substituted by arginine and, in some cases, by serine. As the significance of these residues in terms of interactions with actin remains unclear, the amino acid in this position has not been defined.
Positions 1, 14, 19 and 20 are always occupied by hydrophobic amino acids, usually leucines or isoleucines (as expected based on the hydrophobic character of the interaction, there are some cases of valine and methionine in positions 19 and 20, respectively). The presence of hydrophobic side chains allows the motif to fit into the actin cleft and stabilize the interactions. As the structure in this region forms an alpha-helix, the remaining residues point away from the binding pocket. Proline is disallowed in helix-internal positions.
However, as only five conserved residues within a 20- residue hydrophobic motif were identified, it is particularly prone to false positive bioinformatic predictions buried in globular domains.
|Pattern:||[IL]..[^P][^P][^P][^P]R.....[IL]..[^P][^P][ILV][ILM] (Probability: 0.0000061)|
|Present in taxons:||Fungi Metazoa|
Actin is a core structural component of the cytoskeleton, which owing to its ability to contract, polymerize and interact with a wide range of proteins influences many cellular functions such as the control of cell shape, motility, and polarity, as well as cellular transport. Both formation of filaments, and actin's action as a molecular switch can be regulated by a variety of factors, including interactions with specific motifs, which mediate actin-protein interactions by binding to actin's hydrophobic cleft formed by subdomains 1 and 3.
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