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 133 publications

(191 citation statements)

References 65 publications

(87 reference statements)

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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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“…In general, the lysine (K) residue in the P-loop, together with the main chain amino atoms, is crucial for nucleotide-binding (Hanson & Whiteheart 2005). In the case of RET, the phosphatebinding loop is formed by a sequence motif G-x-G-x-x-GK (Knowles et al 2006), not followed by TS indicating that the conformation of this loop is not subjected potentially to post-translational modification as shown for the case of some bacterial tyrosine kinases (Schumacher et al 2012) and also human DYRK2 (Soundararajan et al 2013). Furthermore, lysine (K737) is not apparently involved in nucleotide coordination, due to redundancy caused by spatial proximity with catalytic K758.…”

Section: Cis-inhibition Of Ret Catalytic Domain By a Tether Between Pmentioning

confidence: 99%

Structure and function of RET in multiple endocrine neoplasia type 2

Plaza-Menacho¹

2018

Endocrine-Related Cancer

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Correspondence should be addressed to I Plaza-Menacho: iplaza@cnio.esThis paper is part of a thematic review section on 25 Years of RET and MEN2. The guest editors for this section were Lois Mulligan and Frank Weber. AbstractIt has been twenty-five years since the discovery of oncogenic germline RET mutations as the cause of multiple endocrine neoplasia type 2 (MEN2). Intensive work over the last two and a half decades on RET genetics, signaling and cell biology has provided the current bases for the genotype-phenotype and functional correlations within this cancer syndrome. On the contrary, the structural and molecular basis for RET tyrosine kinase domain activation and oncogenic deregulation has remained largely elusive. Recent studies with a strong crystallographic and biochemical focus have started to elucidate key insights into such molecular and atomic details revealing unexpected and private mechanisms of actions and molecular determinants not previously envisioned. This review focuses on the structure and function of the RET receptor, and in particular, on what a more detailed view of the protein itself and what the current structural and molecular information tell us about the genotype and phenotype relationships in the cancer syndrome MEN2.

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

Cited by 133 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

Structure and function of RET in multiple endocrine neoplasia type 2

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