MOD_DYRK1A_RPxSP_1

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).