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Abstract
Two missense mutations of the DYRK1B gene have recently been found to co-segregate with a rare autosomal-dominant form of metabolic syndrome. This gene encodes a member of the DYRK family of protein kinases, which depend on tyrosine autophosphorylation to acquire the catalytically active conformation. The mutations (H90P and R102C) affect a structural element named DYRK homology (DH) box and did not directly interfere with the conformation of the catalytic domain in a structural model of DYRK1B. Cellular assays showed that the mutations did not alter the specific activity of mature kinase molecules. However, a significant part of the mutant DYRK1B protein accumulated in detergent-insoluble cytoplasmic aggregates and was underphosphorylated on tyrosine. The mutant DYRK1B variants were more vulnerable to the HSP90 inhibitor ganetespib and showed enhanced binding to the co-chaperone CDC37 as compared to wild type DYRK1B. These results support the hypothesis that the mutations in the DH box interfere with the maturation of DYRK1B by tyrosine autophosphorylation and compromise the conformational stability of the catalytic domain, which renders the kinase susceptible to misfolding.
Highlights
DYRK1B (dual-specificity tyrosine(Y)-phosphorylation regulated kinase 1B) is a member of the DYRK family of protein kinases that attain full catalytic activity by co-translational autophosphorylation on a conserved tyrosine residue in the activation loop of the catalytic domain[1,2,3]
Sequence analysis revealed that the residues affected by the pathogenic mutations belong to a conserved sequence motif designated “DYRK homology box” (DH box) in the N-terminal domain of DYRK1B (Fig. 1A)[1]
In the crystal structure of DYRK1A, the DH box participates in extensive interactions with the catalytic domain[17]
Summary
DYRK1B (dual-specificity tyrosine(Y)-phosphorylation regulated kinase 1B) is a member of the DYRK family of protein kinases that attain full catalytic activity by co-translational autophosphorylation on a conserved tyrosine residue in the activation loop of the catalytic domain[1,2,3]. Affected individuals develop early-onset coronary artery disease, hypertension, central obesity, and diabetes[7]. In contrast to the gain-of-function effects in these cellular assays, DYRK1B-R102C was found to have reduced catalytic activity in in vitro-kinase assays[6], while the effect of the H90P mutation on kinase activity has not yet been studied. Recent findings indicate that the interaction of a kinase with HSP90/CDC37 is not determined by particular sequence motifs, but rather by the conformational status of the catalytic domain[10, 11]. Point mutations can increase or decrease HSP90 interactions with individual kinases in correlation with their effects on the thermodynamic stability of the kinase folds[10, 12, 13]. Amongst the members of the DYRK family, DYRK4 has been classified as a strong HSP90 client, while DYRK1A, DYRK1B and DYRK2 are weak clients[10, 15]
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