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 HePTP class of MAPK docking motifs unifies a few, diverse docking motifs binding to the ERK1/2 and p38 subfamilies of MAPKs (Garai,2012, Zeke,2015). They are structurally united by their helical N-termini and longer internal linkers that also sets them apart from the otherwise similar greater MEF2A class of motifs. They encompass the somewhat shorter Ste7 motif subtype (found in the yeast Ste7 kinase, Msg5 phosphatase and the mammalian RHDF1 and RHDF2 inactive rhomboid proteases) and the longer HePTP subtype (found in several metazoan tyrosine phosphatases and the mammalian ZEP1 transcription factor) (Zeke,2015). In the structure of HePTP bound to ERK2, the HePTP peptide adopts a helical conformation at its N-terminus and the remainder of the peptide is extended. The helix binds to the surface depression between the CD site and the hydrophobic groove while the basic region binds to the CD site and the hydrophobic motif binds to the hydrophobic groove (Zhou,2006), with five residues located in between the two sections. In the docking motifs of the yeast Ste7 and Msg5 proteins, there are only four intervening residues between the basic cluster and the hydrophobic motif as they form a β turn to shorten the intervening region (Remenyi,2005). Due to their altered linker, the helix is also slightly differently positioned than in HePTP. This shorter, Ste7-like arrangement has the consensus [LIV][^P][^P][RK]....[LIVMP].[LIV].[LIVMF], while the similarly helical but slightly longer HePTP-like arrangement comes with the consensus pattern [LIV][^P][^P][RK][RK]G.{4,5}[LIVMP].[LIV].[LIVMF]. In the latter, a conserved glycine is required to terminate the alpha helix. Despite their structural similarity with other D motifs, due to their length and extensive surface contacts, it is difficult to give a single motif definition covering all instances of HePTP-type motifs.
Pattern: ([LIV][^P][^P][RK]....[LIVMP].[LIV].[LIVMF])|([LIV][^P][^P][RK][RK]G.{4,7}[LIVMP].[LIV].[LIVMF])
Pattern Probability: 0.0001066
Present in taxon: Eukaryota
Interaction Domain:
Pkinase (PF00069) Protein kinase domain (Stochiometry: 1 : 1)
o See 10 Instances for DOC_MAPK_HePTP_8
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 4 selected references:

o 12 GO-Terms:

o 10 Instances for DOC_MAPK_HePTP_8
(click table headers for sorting; Notes column: =Number of Switches, =Number of Interactions)
Acc., Gene-, NameStartEndSubsequenceLogic#Ev.OrganismNotes
P08018 PBS2
PBS2_YEAST
217 234 SLSARRGLKLPPGGMSLKMP U 1 Saccharomyces cerevisiae S288c
1 
P35236 PTPN7
PTN7_HUMAN
38 50 HVRLQERRGSNVALMLDVRS TP 6 Homo sapiens (Human)
1 
P15822 HIVEP1
ZEP1_HUMAN
1422 1437 PLLERRRGPLVRQISLNIAP TP 1 Homo sapiens (Human)
2 
Q15256 PTPRR
PTPRR_HUMAN
333 345 PIGLQERRGSNVSLTLDMSS TP 3 Homo sapiens (Human)
1 
P54829 PTPN5
PTN5_HUMAN
239 251 SMGLQERRGSNVSLTLDMCT TP 5 Homo sapiens (Human)
3 
Q62132 Ptprr
PTPRR_MOUSE
332 344 PIGLQERRGSNVSLTLDMSS TP 3 Mus musculus (House mouse)
2 
P06784 STE7
STE7_YEAST
7 19 RKTLQRRNLKGLNLNLHPDV TP 10 Saccharomyces cerevisiae (Baker"s yeast)
3 
P38590 MSG5
MSG5_YEAST
26 38 PRSLQNRNTKNLSLDIAALH TP 4 Saccharomyces cerevisiae (Baker"s yeast)
1 
Q6PJF5 RHBDF2
RHDF2_HUMAN
19 31 SSRLQSRKPPNLSITIPPPE TP 1 Homo sapiens (Human)
1 
Q96CC6 RHBDF1
RHDF1_HUMAN
12 24 TSSLQRKKPPWLKLDIPSAV TP 3 Homo sapiens (Human)
1 
Please cite: The Eukaryotic Linear Motif resource: 2022 release. (PMID:34718738)

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