| Accession: | |
|---|---|
| Functional site class: | MyoX FERM domain binding motif |
| Functional site description: | Myosin X (MyoX), a member of the MyTH4–FERM domain-containing myosins, is characterized by one or a pair of MyTH4–FERM domains at the C-terminal tail region. The integrity of the tandem MyTH4–FERM domains is critical for MyoX’s diverse cellular activities and cargo recognition. MyoX is mainly involved in filopodial induction and elongation, cell adhesion, cell or subcellular structure migrations, and angiogenesis. MyoX uses its FERM region F3 subdomain groove to specifically recognize its target proteins. Only a limited number of SLiM instances are identified for the MyoX FERM domain. A netrin receptor, DCC (deleted in colorectal cancer) is the most studied binding partner. |
| ELM Description: | The MyTH4–FERM tandem domain supramodule of MyoX binds to the P3 motif of DCC. Similar regions are also identified in Neogenin and Frazzled A. The complex structure of MyoX_MF/DCC_P3 (3PZD) shows that the P3 peptide forms a single α-helix and binds to the αβ-groove formed by β5 and α1 of the MyoX FERM F3 lobe. The peptide binding residues are more hydrophobic and are concentrated on the α1 helix. Non-polar interactions via seven conserved hydrophobic residues in the DCC_P3 helix (Leu1423, Met1427, Leu1430, Leu1433, Met1434, Leu1437, and Ile1440) are important for F3 lobe binding (P43146;3AU4). Mutation of either Leu1433 or Leu1437 to alanine in DCC abolished binding. Some polar interactions are also seen, Gln1438 forms a hydrogen bond to the main chain of Phe2002 of the β5C strand that likely helps to orient the helical motif. At the C-terminus, Thr–Gly–Ser form the C-terminal cap of the helix and make a hydrogen bond network to the Lys2034 from the α1C helix (Hirano,2011). As part of the binding partner surface, α1 of the MyoX FERM F3 lobe provides several key interaction spots. Ile2037 from this helix is positioned to form multiple hydrophobic contacts with DCC_P3 and mutating Ile2037Glu leads to loss of DCC_P3 binding to MyoX_MF. It has also been established that Ngn binds to MyoX_MF with similar affinity as for the MyoX_MF/DCC_P3 complex (Wei,2011). Sequence alignments for DCC/Ngn/Frazzled_A show that the region following the motif could be two to six amino acids in length before the protein chain ends at the C-terminus. |
| Pattern: | L...M[^P][^P]L[^P][^P]LM[^P][QD]L[^P][^P]I[TA] |
| Pattern Probability: | 2.012e-12 |
| Present in taxon: | Eukaryota |
| Interaction Domain: |
Myosin X, FERM domain C-lobe (IPR041797)
MyoX, a MyTH-FERM myosin, is a molecular motor that has crucial functions in the transport and/or tethering of integrins in the actin-based extensions known as filopodia, microtubule binding, and in netrin-mediated axon guidance
(Stochiometry: 1 : 1)
|
 Abstract |
The MyTH4–FERM domain-containing myosins, myosin VII, X, and XV are unconventional myosins mainly involved in promoting the formation of filopodia/stereocilia structures in many cell types. Myosin X (MyoX) is the best studied member of the family and is found in all vertebrates. Its tail region contains myosin tail homology 4 (MyTH4) and 4.1/ezrin/radixin/moesin (FERM) domains (the whole module may be abbreviated as MyoX_MF) in tandem that are important for selective cargo recognition. In addition to its role in cargo transportation on actin cables, it is also involved in the faithful chromosome segregation and axon pathfinding of neurons (Hirano,2011). The structural features of its tail region show that these two domains are interconnected by a short linker and form a structural supramodule instead of two separate units. The MyTH4/FERM interaction is critical for maintaining the proper conformation of the F3 lobe and deletion of either of the domains abolishes the MyoX-mediated formation of elongated filopodia. Several cell surface receptors for netrins - Deleted in Colorectal Cancer (DCC), Neogenin (Ngn) and Drosophila Frazzled_A (FzlA) - contain a helical linear motif that specifically binds to the F3 subdomain of FERM. At cellular level, DCC is expressed by commissural axons and thereby acts as a netrin receptor on these axon cells (Keino-Masu,1996). Similar to DCC, Ngn is also involved in the signalling axis elicited via netrins and thus modulates several aspects of development and homeostasis (Wilson,2007). Frazzled is the DCC ortholog in Drosophila and exhibits phenotypes similar to the deletion variants of other netrin genes from Drosophila (Kolodziej,1996). DCC contains four Ig-like domains in the extracellular N-terminal region which are followed by several fibronectin type III (FN) domains and the transmembrane helix. The C-terminal region is located in the cytosolic side and has three conserved sequence stretches, known as DCC P1/P2/P3 (25123307). Structural studies have shown that the groove between the β5C strand and the α1C helix of subdomain F3 of the myosin-X FERM domain acts as a binding site for the DCC P3 helical region (Hirano,2011). The majority of molecular interactions made by the DCC P3 helix are contributed by conserved hydrophobic residues. |
6 selected references:
8 GO-Terms:
4 Instances for LIG_FERM_MyoX_1
(click table headers for sorting; Notes column: =Number of Switches, =Number of Interactions)
| Acc., Gene-, Name | Start | End | Subsequence | Logic | #Ev. | Organism | Notes |
|---|---|---|---|---|---|---|---|
| P43146 DCC DCC_HUMAN |
1425 | 1443 | LSEQMASLEGLMKQLNAITG | TP | 4 | Homo sapiens (Human) | |
| Q92859 NEO1 NEO1_HUMAN |
1441 | 1459 | LTKEMAHLEGLMKDLNAITT | TP | 1 | Homo sapiens (Human) | |
| P70211 Dcc DCC_MOUSE |
1425 | 1443 | LSEQMASLEGLMKQLNAITG | TP | 5 | Mus musculus (House mouse) | |
| Q94538 fra Q94538_DROME |
1502 | 1520 | LNQEMANLEGLMKDLSAITA | TP | 1 | Drosophila melanogaster (Fruit fly) |
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