The Eukaryotic Linear Motif resource for
Functional Sites in Proteins
Functional site class:
MAPK docking motifs
Functional site description:
The MAPK-docking motif, also known as D-motif or kinase interaction motif (KIM) consists of one or more basic and two to four hydrophobic residues in adjacent groups. These residues bind to the MAPK-docking groove in various MAPKs. The basic-hydrophobic pattern can be present either in N- to C-terminal or C- to N-Terminal orientation. A linker region of variable length intersects the basic and hydrophobic residues. This linker region may build secondary structures, like helices, and therefore can add some additional order to the motif bound state. The docking motif patterns vary according to which MAPKs are to be bound. Some docking motifs are quite specific while others are more general.

The binding site of the D-motifs is distinct from another MAPK docking motif class (the FxFP-type), thus they can act in a combinatorial manner.
ELM Description:
The reverse MAPK docking motif is carried by the RSK and MAPKAPK protein families and is well conserved in metazoans. Similar protein families in D. melanogaster or Yeast are also shown to carry a variation. It features a broad range of compositions for the linker between the CD/ED region and hydrophobic docking groove, including local secondary structure, e.g. in helical conformation (Zeke,2015). In some cases removing essential residues of the revD-motif does not prevent phosphorylation of a target protein (Tomas-Zuber,2001). This assumes, that the motif is not exclusively mediating the interaction or a corresponding processing event, in those cases. The revD-motif is present in interaction partners of ERK1/2 and p38. For JNK no interaction partner is shown so far. RevD-motif containing proteins may show preferences to certain kinases. Whereas the RSK1-motif (Q15418) primarily binds ERK2 (P28482), the MK2-motif (P49137) favours p38α (Q16539). However, MSK1 (O75582) and MNK1 (Q9BUB5) equally interact with both, ERK2 and p38α. Discrimination between those kinases is potentially mediated by side chain interactions flanking the motif site or in the linker sequence (Garai,2012).

The reversed motif is composed of 3 hydrophobic residues each separated by 1 or 1/2 arbitrary residues, respectively. A fourth hydrophobic residue completes the hydrophobic part of the motif separated by 4 to 6 variable residues. A positively charged region comprised of 2 residues, being either ARG or LYS, then follows the last hydrophobic residue with fixed spacing. Crystal structures show ordered conformations, such as helical turns, in the motif region (4TYH). This agrees with rather low IUPred values (~0.3) for some residues in a disorder prediction. However, crystal structures indicate that the motif undergoes a disorder-to-order transition upon binding to the docking groove. The binding and specificity to a certain MAPK is enhanced by intra-molecule or intra-peptide H‑bonds.
Pattern: [LIVMPFA].[LIV].{1,2}[LIVMP].{4,6}[LIV]..[RK][RK]
Pattern Probability: 0.0001805
Present in taxon: Eukaryota
Interaction Domain:
Pkinase (PF00069) Protein kinase domain (Stochiometry: 1 : 1)
o See 6 Instances for DOC_MAPK_RevD_3
o Abstract
Classical mitogen-activated protein kinase (MAPK) signalling systems typically consist of three-tiered kinase pathways, with each member activated through phosphorylation by kinases from the preceding layer. These pathways respond to a variety of extracellular challenges involving growth factors, morphogenic signals, biotic and abiotic stress stimuli. Eukaryotic organisms frequently contain multiple MAPK pathways, each responsive for eliciting a specific response to particular upstream signals. Multicellular animals (Metazoa) possess four different groups of classical MAPKs: The ERK1/2 family is responsible for cell cycle progression, growth and differentiation of cells in response to growth factors, also being a key player in the formation of most cancers (Dhillon,2007). In contrast, the JNK and p38 MAPK families are primarily activated by diverse stressors (hyperosmosis, oxidative stress, DNA damage, inflammation, etc.) as well as morphogenes (Cargnello,2011). The single ERK5 protein forms a family of its own, controlling the development of specialized organs (such as the heart and blood vessels Nithianandarajah-Jones,2012). All known MAPKs are serine/threonine kinases, targeting sites followed by a proline ([ST]P consensus). As such sites are extremely common (found in ~80% of all proteins), additional interactions are required to direct the kinase activity towards the correct substrates (Ubersax,2007, Bardwell,2006).
The interacting molecules are kinase substrates, MAPK activators, phosphatases, regulators and adapters (bringing the kinase and the substrate together). One way by which the MAPKs ensure their interaction partner specificity is by interaction through docking motifs, short amino acid stretches located on MAPK-interacting proteins (Bardwell,2003, Bardwell,2001, Sharrocks,2000).
The surface of MAPK kinase domain harbours special binding sites, distinct from the catalytic site, that serve to recruit docking motifs of interaction molecules. The major docking site of MAPKs consists of the hydrophobic docking groove and the adjacent, negatively charged CD (complementary docking) helix, extended by the also negatively charged ED or top site in p38 (Tanoue,2001). Together they recognize the so called D-motifs (named after the D-domain of Elk1, and the δ-domain of c-Jun) of partner proteins, also known as KIMs (kinase interacting motifs Kallunki,1996). D-motifs are intrinsically unstructured linear motifs, typically consisting of one or more positively charged amino acids, followed by a linker and finally three alternating hydrophobic residues. The length and composition of internal linkers is a key determinant in specific interactions of D-motifs with particular MAPKs (Garai,2012). Due to the topography of MAPKs, D-motifs of substrates must be separated from the phosphorylation site by a minimum distance (suggested are ~9 amino acids) for efficient coupling (Fernandes,2007). These docking motifs are most commonly found upstream (N-terminally) from the target phosphorylation sites by approximately 10-100 amino acids, but can be located virtually anywhere in the substrate proteins (Garai,2012, Zeke,2015). Certain interacting molecules do not even possess docking motifs on their own, relying on heterologous interactions with a D-motif containing partner in order to receive phosphorylation from a MAPK.

D-motifs or KIMs are not the only type of MAPK docking motifs. A second docking site of MAPKs (located below the activation loop of the kinase) can recruit the so-called FxFP motifs of substrate proteins. Due to their positioning relative to the catalytic site on the kinase, FxFP motifs are typically found downstream (C-terminally) of phosphorylation sites, often in relative proximity to the target site (5-20 amino acids downstream). Since the FxFP motifs bind to a different surface on the MAPK, they can combine with D-motifs in the same substrate, and act synergistically to enhance phosphorylation. A single substrate protein may contain a D-motif (KIM) or an FxFP motif or both (Galanis,2001, Jacobs,1999).

o 2 selected references:

o 7 GO-Terms:

o 6 Instances for DOC_MAPK_RevD_3
(click table headers for sorting; Notes column: =Number of Switches, =Number of Interactions)
Acc., Gene-, NameStartEndSubsequenceLogic#Ev.OrganismNotes
P18652 RPS6KA
729 743 PSPQLKPIESSILAQRRVKK TP 2 Gallus gallus (Chicken)
O75676 RPS6KA4
717 731 EGFFLKSVENAPLAKRRKQK TP 1 Homo sapiens (Human)
O75582 RPS6KA5
730 744 EGFCLQNVDKAPLAKRRKMK TP 6 Homo sapiens (Human)
434 448 CSMKLSPPCKSRLARRRALA TP 6 Homo sapiens (Human)
Q15418 RPS6KA1
712 726 PTPQLKPIESSILAQRRVRK TP 7 Homo sapiens (Human)
370 386 QIKIKKIEDASNPLLLKRRK TP 9 Homo sapiens (Human)
Please cite: The Eukaryotic Linear Motif resource: 2022 release. (PMID:34718738)

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