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 JIP1 type motifs represent one of the two common docking motif types, primarily mediating interaction with JNK kinases (such as mammalian JNK1, JNK2 or JNK3). (Garai,2012; Zeke,2015). The JNK binding docking motifs are found in their cognate MKK kinases, substrate proteins and scaffold proteins and these sites are not accepted by any other MAPK 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 JIPI type have the motif pattern [RK]P[^P][^P]L.[LIVMF] -while the extended NFAT4-type motifs have an additional hydrophobic residue. The basic residues bind to the corresponding acidic patches in the docking groove in a flexible manner. The bound hydrophobic residues ϕ.ϕ in JIP1 motifs are extensively surrounded by hydrophobic residues from the JNK. The intermediate residue does not make any interaction and has high diversity among MAPK docking motifs. These basic and hydrophobic motifs contain anchor residues that make interactions with the common MAPK surface and provide docking in a non-discriminatory fashion, while the specificity was determined by the conformation of the intervening region between the anchor points. JNK kinases prefer an L.L hydrophobic sub-motif to any other hydrophobic residues at those two positions and its binding affinity can be modulated by changing these hydrophobic residues (Bardwell,2015).
Pattern: [RK]P[^P][^P]L.[LIVMF]
Pattern Probability: 0.0001293
Present in taxon: Metazoa
Interaction Domain:
Pkinase (PF00069) Protein kinase domain (Stochiometry: 1 : 1)
o See 29 Instances for DOC_MAPK_JIP1_4
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 29 Instances for DOC_MAPK_JIP1_4
(click table headers for sorting; Notes column: =Number of Switches, =Number of Interactions)
Acc., Gene-, NameStartEndSubsequenceLogic#Ev.OrganismNotes
Q9UPT6 MAPK8IP3
JIP3_HUMAN
204 210 PGRRKERPTSLNVFPLADGT TP 2 Homo sapiens (Human)
1 
P19419 ELK1
ELK1_HUMAN
315 321 QPQKGRKPRDLELPLSPSLL TP 3 Homo sapiens (Human)
3 
P15336 ATF2
ATF2_HUMAN
165 171 PTSAIVRPASLQVPNVLLTS TP 1 Homo sapiens (Human)
1 
Q9UQF2 MAPK8IP1
JIP1_HUMAN
160 166 DTYRPKRPTTLNLFPQVPRS TP 3 Homo sapiens (Human)
1 
Q9Y566 SHANK1
SHAN1_HUMAN
2016 2022 KVSPAPRPSSLPILPSGPLY TP 2 Homo sapiens (Human)
1 
Q8N2Y8 RUSC2
RUSC2_HUMAN
688 694 RYSKEQRPTTLPIQPFVFQH TP 2 Homo sapiens (Human)
1 
Q13459 MYO9B
MYO9B_HUMAN
1250 1256 RPGQLERPTSLALDSRVSPP TP 4 Homo sapiens (Human)
1 
Q2TAL5 SMTNL2
SMTL2_HUMAN
184 190 PDPPRPRPVSLSLRLPHQPV TP 5 Homo sapiens (Human)
3 
Q9Y6V0 PCLO
PCLO_HUMAN
4269 4275 SSSARTKPTSLPISQSRGRI TP 1 Homo sapiens (Human)
1 
Q8N103 TAGAP
TAGAP_HUMAN
436 442 VQGKTKRPVDLKIKNLAPGS TP 1 Homo sapiens (Human)
1 
Q5JR12 PPM1J
PPM1J_HUMAN
69 75 ARASFSRPTFLQLSPGGLRR TP 3 Homo sapiens (Human)
3 
O35607 Bmpr2
BMPR2_MOUSE
937 943 KPRRAQRPNSLDLSATNILD TP 6 Mus musculus (House mouse)
2 
O35607 Bmpr2
BMPR2_MOUSE
754 760 QQNLPKRPTSLPLNTKNSTK TP 6 Mus musculus (House mouse)
2 
P35570 Irs1
IRS1_RAT
852 858 TNSRLARPTRLSLGDPKAST TP 3 Rattus norvegicus (Norway rat)
Q9Y6W6 DUSP10
DUS10_HUMAN
19 25 ALSRPVRPQDLNLCLDSSYL TP 3 Homo sapiens (Human)
1 
Q9Y2H2 INPP5F
SAC2_HUMAN
1010 1016 TEQTPSRPSQLDVSLSATGP TP 1 Homo sapiens (Human)
1 
Q9UBK2 PPARGC1A
PRGC1_HUMAN
254 260 SQHLQAKPTTLSLPLTPESP TP 1 Homo sapiens (Human)
1 
Q9H7D0 DOCK5
DOCK5_HUMAN
1763 1769 PTRKAQRPKSLQLMDNRLSP TP 2 Homo sapiens (Human)
1 
Q99767 APBA2
APBA2_HUMAN
280 286 PSRHEARPKSLNLLPEAKHP TP 3 Homo sapiens (Human)
1 
Q96N67 DOCK7
DOCK7_HUMAN
885 891 MARSAVRPASLNLNRSRSLS TP 2 Homo sapiens (Human)
1 
Q8WXG6 MADD
MADD_HUMAN
810 816 RAQKLLRPNSLRLASDSDAE TP 1 Homo sapiens (Human)
1 
Q13873 BMPR2
BMPR2_HUMAN
937 943 KPRRAQRPNSLDLSATNVLD TP 1 Homo sapiens (Human)
1 
Q07820 MCL1
MCL1_HUMAN
137 143 PEPLGKRPAVLPLLELVGES TP 1 Homo sapiens (Human)
1 
Q07343 PDE4B
PDE4B_HUMAN
73 79 EGDGISRPTTLPLTTLPSIA TP 2 Homo sapiens (Human)
1 
Q02779 MAP3K10
M3K10_HUMAN
877 883 PPEFPGRPTTLTFAPRPRPA TP 1 Homo sapiens (Human)
1 
P35568 IRS1
IRS1_HUMAN
857 863 TNSRLARPTRLSLGDPKAST TP 2 Homo sapiens (Human)
1 
P17544 ATF7
ATF7_HUMAN
163 169 PTPTIVRPGSLPLHLGYDPL TP 5 Homo sapiens (Human)
2 
O95996 APC2
APC2_HUMAN
963 969 PRCGQPRPSRLDLDLPGCQA TP 1 Homo sapiens (Human)
1 
O60239 SH3BP5
3BP5_HUMAN
343 349 QFPAVVRPGSLDLPSPVSLS TP 8 Homo sapiens (Human)
2 
Please cite: ELM 2016-data update and new functionality of the eukaryotic linear motif resource. (PMID:26615199)

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