Abstract
ABSTRACTHaploinsufficiency of DYRK1A is a cause of a neurodevelopmental syndrome termed mental retardation autosomal dominant 7 (MRD7). Several truncation mutations, microdeletions and missense variants have been identified and result in a recognizable phenotypic profile, including microcephaly, intellectual disability, epileptic seizures, autism spectrum disorder and language delay. DYRK1A is an evolutionary conserved protein kinase which achieves full catalytic activity through tyrosine autophosphorylation. We used a heterologous mammalian expression system to explore the functional characteristics of pathogenic missense variants that affect the catalytic domain of DYRK1A. Four of the substitutions eliminated tyrosine autophosphorylation (L245R, F308V, S311F, S346P), indicating that these variants lacked kinase activity. Tyrosine phosphorylation of DYRK1A-L295F in mammalian cells was comparable to wild type, although the mutant showed lower catalytic activity and reduced thermodynamic stability in cellular thermal shift assays. In addition, we observed that one variant (DYRK1A-T588N) with a mutation outside the catalytic domain did not differ from wild-type DYRK1A in tyrosine autophosphorylation, catalytic activity or subcellular localization. These results suggest that the pathogenic missense variants in the catalytic domain of DYRK1A impair enzymatic function by affecting catalytic residues or by compromising the structural integrity of the kinase domain.This article has an associated First Person interview with the first author of the paper.
Highlights
DYRK1A is a member of the DYRK [dual-specificity tyrosine (Y) phosphorylation-regulated kinase] family of protein kinases which play important roles in the regulation of cell differentiation, proliferation, and survival (Becker and Joost, 1999; Aranda et al, 2011)
Most DYRK1A missense mutations in MRD patients affect the catalytic domain To understand how mental retardation autosomal dominant 7 (MRD7)-linked mutations affect the function of DYRK1A, we compiled a list of pathogenic DYRK1A missense mutations from published reports and the ClinVar and Decipher genome resources (Table 1)
We focused on the other missense mutations (L245R, L295F, F308V, S311F, S346P and R467Q) to explore the structure-function relationship of the DYRK1A catalytic domain
Summary
DYRK1A is a member of the DYRK [dual-specificity tyrosine (Y) phosphorylation-regulated kinase] family of protein kinases which play important roles in the regulation of cell differentiation, proliferation, and survival (Becker and Joost, 1999; Aranda et al, 2011). DYRKs autophosphorylate a critical tyrosine residue in the. The active mature DYRKs phosphorylate serine and threonine residue in a large variety of nuclear and cytoplasmic protein substrates (Aranda et al, 2011; Becker and Sippl, 2011; Tejedor and Hämmerle, 2011). DYRK1A harbors a functional nuclear localization signal and a polyhistidine sequence that targets the protein to the splicing factor compartment (Alvarez et al, 2003)
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
