Structures of Down Syndrome Kinases, DYRKs, Reveal Mechanisms of Kinase Activation and Substrate Recognition

Soundararajan, M.; Roos, A.K.; Savitsky, P.; Filippakopoulos, P.; Kettenbach, Arminja N.; Olsen, Jesper V.; Gerber, Scott A.; Eswaran, Jeyanthy; Knapp, Stefan; Elkins, J.M.

doi:10.1016/j.str.2013.03.012

Cited by 130 publications

(179 citation statements)

References 65 publications

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“…The c.1098+1G>A splice-site mutation is predicted to result in an in-frame deletion of exon 9, which is internal to the protein kinase domain, eliminating several annotated helices and disrupting the critical activation segment that is likely to affect the function of the protein. 16 …”

Section: Resultsmentioning

confidence: 99%

Disruptive de novo mutations of DYRK1A lead to a syndromic form of autism and ID

et al. 2015

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Dual-specificity tyrosine-(Y)-phosphorylation regulated kinase 1A (DYRK1A) maps to the Down syndrome critical region; copy number increase of this gene are thought to play a major role in the neurocognitive deficits associated with Trisomy 21. Truncation of DYRK1A in patients with developmental delay (DD) and autism spectrum disorder (ASD) suggests a different pathology associated with loss-of-function mutations. To understand the phenotypic spectrum associated with DYRK1A mutations, we resequenced the gene in 7,162 ASD/DD patients (2,446 previously reported) and 2,169 unaffected siblings and performed a detailed phenotypic assessment on nine patients. Comparison of our data and published cases with 8,696 controls identified a significant enrichment of DYRK1A truncating mutations (p = 0.00851) and an excess of de novo mutations (p = 2.53×10−10) among ASD/intellectual disability (ID) patients. Phenotypic comparison of all novel (n = 5) and recontacted (n = 3) cases to previous case reports, including larger CNV and translocation events (n = 7), identifies a syndromal disorder among the 15 patients. It is characterized by ID, ASD, microcephaly, intrauterine growth retardation, febrile seizures in infancy, impaired speech, stereotypic behavior, hypertonia, and a specific facial gestalt. We conclude that mutations in DYRK1A define a syndromic form of ASD and ID with neurodevelopmental defects consistent with murine and Drosophila knockout models.

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Section: Resultsmentioning

confidence: 99%

Disruptive de novo mutations of DYRK1A lead to a syndromic form of autism and ID

et al. 2015

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“…Here we identify Y104 and Y111 in the N-terminal region of DYRK1A as sites that are partially (auto-)phosphorylated when DYRK1A is expressed in HeLa cells. We and others have previously identified Y111 as an autophosphorylation site of bacterially expressed DYRK1A [31,33]. Autophosphorylation of these tyrosines may be an ancestral feature of class 1 DYRKs, because Y104 and Y111 are extremely well conserved even in very distantly related unicellular eukaryotes including slime mould (Dictyostelium) and the flagellate Trypanosoma (see Fig.…”

Section: Tyrosine Kinase Activity Of Dyrks Is Not Limited To the Consmentioning

confidence: 97%

Mechanism of dual specificity kinase activity of DYRK1A

et al. 2013

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The function of many protein kinases is controlled by the phosphorylation of a critical tyrosine residue in the activation loop. Dual specificity tyrosinephosphorylation-regulated kinases (DYRKs) autophosphorylate on this tyrosine residue but phosphorylate substrates on aliphatic amino acids. This study addresses the mechanism of dual specificity kinase activity in DYRK1A and related kinases. Tyrosine autophosphorylation of DYRK1A occurred rapidly during in vitro translation and did not depend on the non-catalytic domains or other proteins. Expression in bacteria as well as in mammalian cells revealed that tyrosine kinase activity of DYRK1A is not restricted to the co-translational autophosphorylation in the activation loop. Moreover, mature DYRK1A was still capable of tyrosine autophosphorylation. Point mutants of DYRK1A and DYRK2 lacking the activation loop tyrosine showed enhanced tyrosine kinase activity. A series of structurally diverse DYRK1A inhibitors was used to pharmacologically distinguish different conformational states of the catalytic domain that are hypothesized to account for the dual specificity kinase activity. All tested compounds inhibited substrate phosphorylation with higher potency than autophosphorylation but none of the tested inhibitors differentially inhibited threonine and tyrosine kinase activity. Finally, the related cyclin-dependent kinase-like kinases (CLKs), which lack the activation loop tyrosine, autophosphorylated on tyrosine both in vitro and in living cells. We propose a model of DYRK autoactivation in which tyrosine autophosphorylation in the activation loop stabilizes a conformation of the catalytic domain with enhanced serine/threonine kinase activity without disabling tyrosine phosphorylation. The mechanism of dual specificity kinase activity probably applies to related serine/threonine kinases that depend on tyrosine autophosphorylation for maturation. Structured digital abstract• CLK1 and CLK1 phosphorylate by protein kinase assay (View interaction)• HIPK2 and HIPK2 phosphorylate by protein kinase assay (View interaction)• DYRK1A phosphorylates SF3B1 by protein kinase assay (View interaction)• DYRK1A and DYRK1A phosphorylate by protein kinase assay (View interaction)

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“…Similarly to other so-called proline-directed serine-threonine kinases, the substrate binding pocket of MAPKs accepts serine or threonine residues that are followed by a proline (S/TP motifs). Because proline-directed kinases presumably bind their substrates similarly, an optimal distance for the two critical ERK2 and RSK1 residues could be obtained based on a related proline-directed kinasesubstrate complex structure (14). The Thr-Pro motif region of the RSK1 activation loop was superimposed with the corresponding residues from the DYRK1A-substrate peptide complex and the loop conformation was minimized (SI Appendix, Fig.…”

Section: Significancementioning

confidence: 99%

Structural assembly of the signaling competent ERK2–RSK1 heterodimeric protein kinase complex

Alexa

Gógl

Glatz

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Mitogen-activated protein kinases (MAPKs) bind and activate their downstream kinase substrates, MAPK-activated protein kinases (MAPKAPKs). Notably, extracellular signal regulated kinase 2 (ERK2) phosphorylates ribosomal S6 kinase 1 (RSK1), which promotes cellular growth. Here, we determined the crystal structure of an RSK1 construct in complex with its activator kinase. The structure captures the kinase-kinase complex in a precatalytic state where the activation loop of the downstream kinase (RSK1) faces the enzyme's (ERK2) catalytic site. Molecular dynamics simulation was used to show how this heterodimer could shift into a signaling-competent state. This structural analysis combined with biochemical and cellular studies on MAPK→MAPKAPK signaling showed that the interaction between the MAPK binding linear motif (residing in a disordered kinase domain extension) and the ERK2 "docking" groove plays the major role in making an encounter complex. This interaction holds kinase domains proximal as they "readjust," whereas generic kinase domain surface contacts bring them into a catalytically competent state.protein kinase | signal transduction | structural biology | ERK2 | RSK1

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Structures of Down Syndrome Kinases, DYRKs, Reveal Mechanisms of Kinase Activation and Substrate Recognition

Cited by 130 publications

References 65 publications

Disruptive de novo mutations of DYRK1A lead to a syndromic form of autism and ID

Disruptive de novo mutations of DYRK1A lead to a syndromic form of autism and ID

Mechanism of dual specificity kinase activity of DYRK1A

Structural assembly of the signaling competent ERK2–RSK1 heterodimeric protein kinase complex

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