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_GRA24_9  DOC_MAPK_HePTP_8  DOC_MAPK_JIP1_4  DOC_MAPK_MEF2A_6  DOC_MAPK_NFAT4_5  DOC_MAPK_RevD_3 
ELM Description:
The greater DCC class of MAPK docking motifs mediate interaction towards the ERK1/2 and p38 subfamilies of MAP kinases. (Zeke,2015). The first members of this family were identified in the human Deleted in Colorectal Cancer (DCC) and the yeast FAR1 proteins. Known partners of DCC class docking motifs include the mammalian ERK1 (MAPK3), ERK2 (MAPK1), p38α (MAPK14) and p38β (MAPK11) protein kinases. They may also bind other partners, and are encountered in fungi and presumably also in higher plants, interacting with diverse MAPKs (Kusari,2004; Petersen,2011). Since the CD region of ERK and p38 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. DCC-type docking motifs have the consensus [RK].{2, 4}[LIVP]P.[LIV].[LIVMF] or [RK].{2, 4}[LIVP].P[LIV].[LIVMF], with three hydrophobic contact points (ϕL = Leu/Ile/Val/Pro, ϕA = Leu/Ile/Val and ϕB = Leu/Ile/Val/Met/Phe) binding the surface of the targeted MAPKs, similarly to the related MEF2A-type motifs. But unlike the fully extended MEF2A-type docking motifs, DCC-type motifs partly adopt a type II polyproline helix-like geometry. The 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 (Ma,2010). Most motif instances feature multiple positively charged residues (Arg/Lys) on their N-termini, but their relative positioning is quite variable. Similarly, all known examples seem to require one or two proline amino acids internally, probably to support the type II polyproline helix-like geometry. These additional prolines might be found immediately after the first hydrophobic (ϕL) position (as in DCC or MEK2) or one amino acid downstream (as in FAR1) and do not make direct contact towards the surface of MAPKs (Ma,2010; Gogl,2013; Remenyi,2005).
Pattern: [RK].{2,4}[LIVP]P.[LIV].[LIVMF]|[RK].{2,4}[LIVP].P[LIV].[LIVMF]
Pattern Probability: 0.0004513
Present in taxon: Eukaryota
Interaction Domain:
Pkinase (PF00069) Protein kinase domain (Stochiometry: 1 : 1)
o See 11 Instances for DOC_MAPK_DCC_7
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 6 selected references:

o 11 GO-Terms:

o 11 Instances for DOC_MAPK_DCC_7
(click table headers for sorting; Notes column: =Number of Switches, =Number of Interactions)
Acc., Gene-, NameStartEndSubsequenceLogic#Ev.OrganismNotes
P21268 FAR1
FAR1_YEAST
73 82 LMMSKRGNIPKPLNLSKPIS TP 5 Saccharomyces cerevisiae S288c
1 
Q13191 CBLB
CBLB_HUMAN
491 499 LAQRRKPQPDPLQIPHLSLP TP 1 Homo sapiens (Human)
1 
Q96PN7 TRERF1
TREF1_HUMAN
655 663 EKKKFRHRPEPLFIPPPPSY TP 1 Homo sapiens (Human)
1 
Q6PJG2 ELMSAN1
EMSA1_HUMAN
603 611 RKPKQRPRPEPLIIPTKAGT TP 1 Homo sapiens (Human)
1 
Q13480 GAB1
GAB1_HUMAN
527 536 NLKPDRKVKPAPLEIKPLPE TP 1 Homo sapiens (Human)
1 
Q03063 DIG1
DIG1_YEAST
98 107 KKSLKRGRVPAPLNLSDSNT TP 3 Saccharomyces cerevisiae (Baker"s yeast)
2 
D2KU33 NbWRKY8
D2KU33_NICBE
52 61 GIPKFKSLPPPSLPLSPPPF TP 5 Nicotiana benthamiana
3 
Q03373 DIG2
DIG2_YEAST
102 110 HSLKRKRVPPALNFSDIQAS TP 4 Saccharomyces cerevisiae (Baker"s yeast)
2 
P43146 DCC
DCC_HUMAN
1146 1155 RKGSQKDLRPPDLWIHHEEM TP 1 Homo sapiens (Human)
1 
Q63155 Dcc
DCC_RAT
1146 1155 RKGSQKDLRPPDLWIHHEEM TP 5 Rattus norvegicus (Norway rat)
1 
O43497 CACNA1G
CAC1G_HUMAN
1033 1041 HPELRKSLLPPLIIHTAATP TP 1 Homo sapiens (Human)
1 
Please cite: The Eukaryotic Linear Motif resource: 2022 release. (PMID:34718738)

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