The Eukaryotic Linear Motif resource for
Functional Sites in Proteins
Accession:
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.
ELMs with same func. site: DOC_MAPK_DCC_7  DOC_MAPK_FxFP_2  DOC_MAPK_gen_1  DOC_MAPK_HePTP_8  DOC_MAPK_JIP1_4  DOC_MAPK_MEF2A_6  DOC_MAPK_NFAT4_5  DOC_MAPK_RevD_3 
ELM Description:
MAPK interacting molecules (e.g. MAPKKs, substrates, phosphatases) carry docking motifs that help to regulate specific interactions in the MAPK cascade. The FXFP motif was first identified in the transcription factor LIN-1 (Jacobs,1998). It is usually found C-terminal of the phosphorylation site. Binding and substrate phosphorylation can occur also in the absence of the proline residue; however its presence increases the binding affinity (Jacobs,1999; Fantz,2001).
Pattern: F.[FY]P
Pattern Probability: 0.0000563
Present in taxon: Eukaryota
Interaction Domain:
Pkinase (PF00069) Protein kinase domain (Stochiometry: 1 : 1)
o See 15 Instances for DOC_MAPK_FxFP_2
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 9 selected references:

o 6 GO-Terms:

o 15 Instances for DOC_MAPK_FxFP_2
(click table headers for sorting; Notes column: =Number of Switches, =Number of Interactions)
Acc., Gene-, NameStartEndSubsequenceLogic#Ev.OrganismNotes
Q9R1Z8 Sorbs3
VINEX_MOUSE
630 633 RTSPRRSAFPFPITLQEPRS TP 5 Mus musculus (House mouse)
1 
P28562 DUSP1
DUS1_HUMAN
339 342 RGTSTTTVFNFPVSIPVHST TP 5 Homo sapiens (Human)
1 
A6X8Z5 Arhgap31
RHG31_MOUSE
677 680 IPESSPAPFPFPEAPGSLPS TP 1 Mus musculus (House mouse)
1 
P11308-3 ERG
ERG_HUMAN
236 239 ARNTGGAAFIFPNTSVYPEA TP 3 Homo sapiens (Human)
1 
Q03063 DIG1
DIG1_YEAST
412 415 RLSSHIFAFEFPLSSSNVDK TP 3 Saccharomyces cerevisiae (Baker"s yeast)
2 
G5EFD2 ksr-1
G5EFD2_CAEEL
309 312 SRSMNEPAFQFPDTAIDSSS TP 4 Caenorhabditis elegans
1 
P47930 Fosl2
FOSL2_MOUSE
282 285 TPGTSNLVFTYPNVLEQESP TP 2 Mus musculus (House mouse)
P48755 Fosl1
FOSL1_MOUSE
237 240 TPFTPSLVFTYPSTPEPCSS TP 2 Mus musculus (House mouse)
P01100 FOS
FOS_HUMAN
343 346 TAYTSSFVFTYPEADSFPSC TP 4 Homo sapiens (Human)
2 
P28324 ELK4
ELK4_HUMAN
398 401 RLQGANTLFQFPSVLNSHGP TP 3 Homo sapiens (Human)
Q61097 Ksr1
KSR1_MOUSE
471 474 SPGQRDSRFSFPDISACSQA TP 2 Mus musculus (House mouse)
1 
G5EDL0 lin-1
G5EDL0_CAEEL
381 384 PGLGESQVFQFPPVSAFQAT TP 1 Caenorhabditis elegans
1 
P19419 ELK1
ELK1_HUMAN
395 398 PRSPAKLSFQFPSSGSAQVH TP 2 Homo sapiens (Human)
1 
G5EDL0 lin-1
G5EDL0_CAEEL
420 423 PPSQSSTSFKFPSSTDSLKT TP 2 Caenorhabditis elegans
P23396 RPS3
RS3_HUMAN
77 80 LTAVVQKRFGFPEGSVELYA FP 3 Homo sapiens (Human)
Please cite: ELM 2016-data update and new functionality of the eukaryotic linear motif resource. (PMID:26615199)

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