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:
The greater MEF2A class of MAPK docking motifs mediates interaction towards the ERK1/2 and p38 subfamily of MAP kinases. (Garai,2012, Zeke,2015). Known partners include the mammalian ERK1 (MAPK3), ERK2 (MAPK1), p38α (MAPK14) and p38β (MAPK11) proteins. They may also bind other classical MAPKs, including the mammalian ERK5 (MAPK7) (Barsyte-Lovejoy,2004). MEF2A-type motifs motifs are also found in fungi and higher plants, interacting with diverse MAPKs (Jung,2002; Hamel,2011). Since the CD region of ERK1/2 and p38 isoforms is wider compared to that of JNK, the N‐termini of motifs binding to these kinases have larger conformational freedom and can make different motif patterns. MEF2A type motifs have the consensus sequence [RK].{2,4}[LIVMP].[LIV].[LIVMF], binding with an extended conformation into the docking groove (Zhou,2006). Typically three hydrophobic amino acids contact the surface (ϕL = Leu/Ile/Val/Met/Pro, ϕA = Leu/Ile/Val and ϕB = Leu/Ile/Val/Met/Phe). This hydrophobic C-terminus is usually locked into a single conformation in the bound state, whereas the charged N terminus might still remain as an ensemble of multiple conformations, invisible to X-ray crystallography (Garai,2012). Most motif instances feature multiple positively charged residues (Arg/Lys) on their N-termini, but their relative positioning is quite variable. Many (but not all) members also display a conserved Pro amino acid after the last hydrophobic position (ϕB) that can form an additional hydrophobic interaction towards the surface of p38α as in the case of human TAB1, MEF2A and MKK6 proteins ( De Nicola,2013; Chang,2002; Garai,2012).
Pattern: [RK].{2,4}[LIVMP].[LIV].[LIVMF]
Pattern Probability: 0.0025838
Present in taxon: Eukaryota
Interaction Domain:
Pkinase (PF00069) Protein kinase domain (Stochiometry: 1 : 1)
o See 24 Instances for DOC_MAPK_MEF2A_6
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 8 selected references:

o 13 GO-Terms:

o 24 Instances for DOC_MAPK_MEF2A_6
(click table headers for sorting; Notes column: =Number of Switches, =Number of Interactions)
Acc., Gene-, NameStartEndSubsequenceLogic#Ev.OrganismNotes
P45985 MAP2K4
MP2K4_HUMAN
41 48 SSMQGKRKALKLNFANPPFK TP 1 Homo sapiens (Human)
1 
Q9ULG1 INO80
INO80_HUMAN
1320 1329 DGKRRKEGVNLVIPFVPSAD TP 1 Homo sapiens (Human)
1 
Q9UGJ0 PRKAG2
AAKG2_HUMAN
30 37 KNASQKRRSLRVHIPDLSSF TP 3 Homo sapiens (Human)
1 
Q8WWW8 GAB3
GAB3_HUMAN
366 374 QSLRHRDKRLSLNLPCRFSP TP 2 Homo sapiens (Human)
1 
Q8NEZ4 KMT2C
KMT2C_HUMAN
1201 1208 PRRKRSKPKLKLKIINQNSV TP 1 Homo sapiens (Human)
1 
Q86VZ6 JAZF1
JAZF1_HUMAN
79 88 ESLKKKIQPKLSLTLSSSVS TP 2 Homo sapiens (Human)
1 
Q6VAB6 KSR2
KSR2_HUMAN
333 341 PKAKKKSKPLNLKIHSSVGS TP 3 Homo sapiens (Human)
1 
Q63HK5 TSHZ3
TSH3_HUMAN
323 330 IPATRKKASLELELPSSPDS TP 1 Homo sapiens (Human)
1 
Q01432 AMPD3
AMPD3_HUMAN
82 90 SFKMIRSQSLSLQMPPQQDW TP 1 Homo sapiens (Human)
1 
P57682 KLF3
KLF3_HUMAN
90 97 FPSSHRRASPGLSMPSSSPP TP 1 Homo sapiens (Human)
1 
P52564 MAP2K6
MP2K6_HUMAN
7 15 SQSKGKKRNPGLKIPKEAFE TP 2 Homo sapiens (Human)
1 
P23109 AMPD1
AMPD1_HUMAN
113 121 RFQGRKTVNLSIPLSETSST TP 1 Homo sapiens (Human)
1 
O60583 CCNT2
CCNT2_HUMAN
501 509 ADKKEKSGSLKLRIPIPPTD TP 2 Homo sapiens (Human)
1 
Q8CF89 Tab1
TAB1_MOUSE
400 409 AQSTSKTSVTLSLVMPSQGQ TP 5 Mus musculus (House mouse)
1 
Q15750-1 TAB1
TAB1_HUMAN
402 411 AQSTSKTSVTLSLVMPSQGQ TP 3 Homo sapiens (Human)
1 
Q9FX43 MKK9
M2K9_ARATH
7 16 ALVRERRQLNLRLPLPPISD TP 3 Arabidopsis thaliana (Thale cress)
2 
Q9LPQ3 MKK7
M2K7_ARATH
7 16 ALVRKRRQINLRLPVPPLSV TP 3 Arabidopsis thaliana (Thale cress)
2 
Q8RXG3 MKK5
M2K5_ARATH
21 28 KNRLRKRPDLSLPLPHRDVA TP 3 Arabidopsis thaliana (Thale cress)
2 
O80397 MKK4
M2K4_ARATH
21 28 KSRPRRRPDLTLPLPQRDVS TP 3 Arabidopsis thaliana (Thale cress)
2 
G8IEK9 C2H2-type zinc finger protein 1
G8IEK9_POPTR
148 156 RSNSRRVLCLDLNLTPYEND TP 6 Populus trichocarpa (Black cottonwood)
Q12224 RLM1
RLM1_YEAST
317 326 VKARRKLSARPVLRVRIPNN TP 1 Saccharomyces cerevisiae S288c
1 
Q02078 MEF2A
MEF2A_HUMAN
270 277 LGMNSRKPDLRVVIPPSSKG TP 6 Homo sapiens (Human)
1 
Q06413 MEF2C
MEF2C_HUMAN
251 259 LGMNNRKPDLRVLIPPGSKN TP 4 Homo sapiens (Human)
O43353 RIPK2
RIPK2_HUMAN
327 335 HLCDKKKMELSLNIPVNHGP TP 1 Homo sapiens (Human)
1 
Please cite: ELM 2016-data update and new functionality of the eukaryotic linear motif resource. (PMID:26615199)

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