The Eukaryotic Linear Motif resource for
Functional Sites in Proteins
Accession:
Functional site class:
MOD_DYRK1A_RPxSP_1
Functional site description:
The Dual specificity tYrosine-phosphorylation Regulated protein Kinases (DYRKs) are a small family within the group of proline-directed kinases. The best studied member, DYRK1A, recognizes a consensus motif RPxSP. For Serine-Threonine kinases, DYRKs are unusual in being able to autophosphorylate a tyrosine residue.
The DYRKs gain their full catalytic activity upon auto-phosphorylation of the second tyrosine residue in the YxY motif in the activation loop (Aranda,2011). The most studied member of the DYRK family is the DYRK1A for which (Himpel,2000) provides a phosphorylation spot assay. There are no spot assays present for other members, but evidence from several papers reveal a less strict preference of the DYRK class 2 for Proline at +1 position, and Arginine at -3 position, rather phosphorylating a motif with Arginine located from 1 to 4 residues upstream of the phosphorylated Serine/Threonine. Currently only DYRK1 has an entry in ELM.
ELM Description:
DYRK1A optimally phosphorylates sites that are close to the consensus RPx(ST)P. The motif pattern in ELM is mainly based on the SPOT array data (Himpel,2000). DYRKs can phosphorylate Serine and Threonine in the consensus motif sequence, starting with Arginine at -3 position, at -2 position it has a strong preference for Proline, although there are other residues as Alanine, Serine and Valine that are recognised in some substrates, other residues are avoided. There is no strong amino acid preference for the -1 position. +1 has a strong preference for proline. Although many non-consensus sites are reported, the ELM motif does not consider them. Perhaps of significance, the only peptide that would co-crystallise with DYRK1 has the optimal sequence (Soundararajan,2013). The Proline at the P+1 position binds against the auto-phosphorylated pTyr321; Arginine at -3 position binds to the negatively charged pocket in the C lobe formed by Glu291, Tyr327, Tyr246 and Glu353.
Pattern: R[PSVA].([ST])P
Pattern Probability: 0.0003132
Present in taxon: Eukaryota
Interaction Domain:
Pkinase (PF00069) Protein kinase domain (Stochiometry: 1 : 1)
o See 22 Instances for MOD_DYRK1A_RPxSP_1
o Abstract
The DYRK protein family is a family of dual specificity tyrosine phosphorylation regulated kinases whose substrates are phosphorylated on serines and threonines.
The unique feature of the family is the ability to auto-phosphorylate the second Tyrosine in the conserved YxY motif (Tyr321 for DYRK1A and Tyr309 for DYRK2) in the activation loop (Lochhead,2005). Once the protein has been phosphorylated, the protein gains its full kinase activity. DYRKs are expected to be in all eukaryotes (Aranda,2011). Yeast Yak1 was identified as a negative growth regulator of Saccharomyces cerevisiae cell cycle, shuttling between cytosol and nucleus dependent upon glucose availability (Moriya,2001). Drosophila DYRK minibrain gene mutants have reduced brain sizes (Tejedor,1995). There are 5 mammalian DYRK family members and they are divided into 2 classes. DYRK class 1 includes 2 members: DYRK1A and DYRK1B; class 2 includes 3 members: DYRK2, DYRK3, and DYRK4.
On the structural level, all DYRKs share the conserved kinase domain preceded by DYRK homology box (DH box). There is a PEST region in the C-terminal IDP segment and the Nuclear localization signal (NLS) in the N-terminal region are conserved in members of class 1, while the second class shares the N-terminal auto-phosphorylation accessory (NAPA) domain (Aranda,2011).
The most studied and the only one member of this family to have a spot assay is the DYRK1A. According to the spot assay provided by (Himpel,2000) DYRK1A recognizes the substrate motif of the R[PSAV].[ST]P consensus sequence. There are no spot assays available for other members, but the evidence coming from several research articles reveal less strict preference of the DYRK class 2 for Proline at +1 position, rather tolerating Valine at P+1 (Campbell,2002, Nishi,2005).
Co-crystallization of an optimal RPgTP peptide with DYRK1A (pdb:2w06) provides an insight of the mechanism of substrate binding. Characteristic for the motif Proline at P+1 position binds against the auto-phosphorylated pTyr321, Arginine at -3 position binds to the negatively charged pocket in the C lobe formed by Glu291, Tyr327, Tyr246 and Glu353 (Soundararajan,2013).
DYRK1A so far has various cellular functions collected into several areas such as cell survival, cell differentiation, gene transcription and endocytosis (Aranda,2011). According to the substrates phosphorylated by DYRK1A, the following functions were associated with the DYRK1A. Androgen and glucocorticoid-mediated transcription stimulation (by phosphorylation of Arip4 by DYRK1A) (Sitz,2004); stimulation of neuronal differentiation by up-regulating the Ras/MAP signaling pathway through phosphorylation of MAP2K1 (Kelly,2005); phosphorylation of septin4 was found to have an association with neuropathologies such as Down syndrome and Alzheimer’s disease (Sitz,2008); phosphorylated amphiphysin both enhances the binding to Grb2, reduces interaction with endophilin, and both enhances and reduces binding to dynamin, thus controlling the assembly of the endocytic complexes (Murakami,2006); phosphorylation of caspase 9 indicates the role in apopototic regulation by DYRK1A (Laguna,2008) .
DYRKs have a clinical significance as well. Trisomy 21 is associated with increased DYRK1A protein level. Mouse mutants with knocked out DYRK genes result in microcephaly, growth retardation, and developmental delay. The gene knockouts in mice revealed the essential survival role for DYRK1A and nonessential role for DYRK3 and 4 (Aranda,2011). Tau, one of the substrate proteins phosphorylated by DYRK1A is associated with tauopathy and Alzheimer’s disease (Ferrer,2005). Owing to the clinical significance of DYRK1A, specific inhibitors are an active area of research. Harmine is known as an ATP-competitive inhibitor able to inhibit DYRK1A, 1B, 2 and 3, with the strongest sensitivity to DYRK1A (Aranda,2011).
o 5 selected references:

o 25 GO-Terms:

o 22 Instances for MOD_DYRK1A_RPxSP_1
(click table headers for sorting; Notes column: =Number of Switches, =Number of Interactions)
Acc., Gene-, NameStartEndSubsequenceLogic#Ev.OrganismNotes
O76039 CDKL5
CDKL5_HUMAN
717 721 RRVGSFYRVPSPRPDNSFHE TP 6 Homo sapiens (Human)
Q64350 Eif2b5
EI2BE_RAT
536 540 DPEELDSRAGSPQLDDIRVF TP 4 Rattus norvegicus (Norway rat)
Q07955 SRSF1
SRSF1_HUMAN
224 228 SRSNSRSRSYSPRRSRGSPR TP 5 Homo sapiens (Human)
P10636-8 MAPT
TAU_HUMAN
209 213 SPGTPGSRSRTPSLPTPPTR TP 9 Homo sapiens (Human)
P55211 CASP9
CASP9_HUMAN
122 126 IRKPEVLRPETPRPVDIGSG U 9 Homo sapiens (Human)
Q8NCN4 RNF169
RN169_HUMAN
400 404 PKRLPDGRVLSPLIIKSTPR TP 6 Homo sapiens (Human)
Q8NCN4 RNF169
RN169_HUMAN
365 369 ASLHKPERSVSPESNDSISE TP 6 Homo sapiens (Human)
O95644 NFATC1
NFAC1_HUMAN
258 262 WLGARSSRPASPCNKRKYSL TP 3 Homo sapiens (Human)
Q7TQF7 Amph
AMPH_MOUSE
290 294 PASPAPVRPRSPSQTRKGPP TP 5 Mus musculus (House mouse)
P49418 AMPH
AMPH_HUMAN
290 294 PASPAPARPRSPSQTRKGPP TP 8 Homo sapiens (Human)
P39053-4 Dnm1
DYN1_MOUSE
854 858 SRSGQASPSRPESPRPPFDL TP 3 Mus musculus (House mouse)
P21575 Dnm1
DYN1_RAT
854 858 SRSGQASPSRPESPRPPFDL TP 12 Rattus norvegicus (Norway rat)
Q02363 ID2
ID2_HUMAN
24 28 DHSLGISRSKTPVDDPMSLL TP 6 Homo sapiens (Human)
Q16629 SRSF7
SRSF7_HUMAN
230 234 KRSRSPSGSPRRSASPERMD TP 7 Homo sapiens (Human)
Q16629 SRSF7
SRSF7_HUMAN
214 218 RSSRSKSRSPSPKRSRSPSG TP 7 Homo sapiens (Human)
Q13247 SRSF6
SRSF6_HUMAN
300 304 SRSRSQSRSNSPLPVPPSKA TP 5 Homo sapiens (Human)
O43236 SEPTIN4
SEPT4_HUMAN
104 108 APLSPSARPRSPWGKLDPYD TP 5 Homo sapiens (Human)
Q01986 Map2k1
MP2K1_RAT
289 293 DAAETPPRPRTPGRPLSSYG TP 3 Rattus norvegicus (Norway rat)
Q96S94 CCNL2
CCNL2_HUMAN
424 428 SQSRSRSRSDSPPRQAPRSA U 7 Homo sapiens (Human)
1 
Q96S94 CCNL2
CCNL2_HUMAN
397 401 SYSRSPSRSASPKRRKSDSG U 7 Homo sapiens (Human)
1 
Q99NG0 Rad54l2
ARIP4_MOUSE
1165 1169 PDPEGLARPVSPDSPEIISE TP 1 Mus musculus (House mouse)
Q9Y4B4 RAD54L2
ARIP4_HUMAN
1166 1170 PDPEGLARPVSPDSPEIISE TP 3 Homo sapiens (Human)
Please cite: The eukaryotic linear motif resource - 2018 update. (PMID:29136216)

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