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 NFAT4 variant represents one of the two MAPK docking motif types that primarily mediate interaction with JNK kinases (such as mammalian JNK1, JNK2 or JNK3). (Garai,2012, Zeke,2015). The JNK binding docking motifs are specific to their cognate MKK kinases, substrate proteins and scaffold proteins and these sites are not bound by any other MAP kinases. In JNKs, the charged CD groove lies closer to the hydrophobic pockets and the surface is less negatively charged compared to other MAP kinases so only a single R/K is required, setting them apart from other MAPKs and providing specificity on docking (Garai,2012). There exist two types of JNK-binding D motifs. The shorter JIP1 type and the extended NFAT4 type. The NFAT4 type has the motif pattern [RK][^P][^P][LIM].L.[LIVMF]. The basic residue is required but, compared to JIP1, makes looser and less well-defined contacts with the surface of JNK. While the three hydrophobic residues occupy the three hydrophobic depressions on the surface of JNK and provide stronger binding (Bardwell,2015). The intervening region forms a small helical turn and Pro is strongly disfavoured in this region as it destroys the formation of a short alpha-helical main-chain conformation that gives specificity to NFAT4-type binding mode (Garai,2012).

Pattern: [RK][^P][^P][LIM].L.[LIVMF].
Pattern Probability: 0.0001635
Present in taxon: Metazoa
Interaction Domain:
Pkinase (PF00069) Protein kinase domain (Stochiometry: 1 : 1)
o See 17 Instances for DOC_MAPK_NFAT4_5
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 22800864). 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 (17918909). 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 12 selected references:

o 22 GO-Terms:

o 17 Instances for DOC_MAPK_NFAT4_5
(click table headers for sorting; Notes column: =Number of Switches, =Number of Interactions)
Acc., Gene-, NameStartEndSubsequenceLogic#Ev.OrganismNotes
206 214 SNAGGKRKLSLMLDEGSSCP TP 1 Homo sapiens (Human)
574 582 FPEPSKQNLSLKLTKDVDQE TP 1 Homo sapiens (Human)
13 21 AIAAEKEALNLKLPPIVHLP TP 1 Homo sapiens (Human)
673 681 REKSNRSELYLDLHPDHSLT TP 1 Homo sapiens (Human)
245 253 TAGRGRSELCLDLPDPPEDP TP 1 Homo sapiens (Human)
323 331 PATRKKASLELELPSSPDST TP 1 Homo sapiens (Human)
507 515 SVSRGRADLSLDLTSPAAPA TP 1 Homo sapiens (Human)
Q13233 MAP3K1
1078 1086 QGDPSKNSMTLDLNSSSKCD TP 1 Homo sapiens (Human)
O43353 RIPK2
326 334 IHLCDKKKMELSLNIPVNHG TP 1 Homo sapiens (Human)
P05412 JUN
35 43 NPKILKQSMTLNLADPVGSL TP 4 Homo sapiens (Human)
Q12968 NFATC3
146 154 LERPSRDHLYLPLEPSYRES TP 7 Homo sapiens (Human)
Q13023 AKAP6
434 442 VDPPDRSKLCLVLQSSYPNS TP 4 Homo sapiens (Human)
P17535 JUND
47 55 GSMMKKDALTLSLSEQVAAA TP 1 Homo sapiens (Human)
P15066 Jund
52 60 SSMLKKDALTLSLAEQGAAG TP 3 Mus musculus (House mouse)
O60336 MAPKBP1
1293 1301 LALPSRAHLVLDIPKPLPDR TP 1 Homo sapiens (Human)
Q6NS57 Mapkbp1
1282 1290 LALPSRAHLVLDIPKPLPDR TP 3 Mus musculus (House mouse)
P45985 MAP2K4
41 49 SMQGKRKALKLNFANPPFKS TP 7 Homo sapiens (Human)
Please cite: ELM 2016-data update and new functionality of the eukaryotic linear motif resource. (PMID:26615199)

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