DYRK1B mutations associated with metabolic syndrome impair the chaperone-dependent maturation of the kinase domain.
DYRK1B mutations associated with metabolic syndrome impair the chaperone-dependent maturation of the kinase domain.
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DOI：
10.1038/s41598-017-06874-w
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发表时间：
2017-07-25
影响因子：
4.6
通讯作者：
Becker W
中科院分区：
文献类型：
--
作者：
Abu Jhaisha S;Widowati EW;Kii I;Sonamoto R;Knapp S;Papadopoulos C;Becker W
最近发现DYRK1B基因的两个错义突变与一种罕见的常染色体显性形式的代谢综合征共分离。该基因编码蛋白激酶DYRK家族的成员，其依赖于酪氨酸自磷酸化以获得催化活性构象。突变（H90 P和R102 C）影响名为DYRK同源（DH）盒的结构元件，并没有直接干扰DYRK1B结构模型中催化结构域的构象。细胞分析表明，突变并没有改变成熟激酶分子的比活性。然而，一个显着的一部分的突变DYRK1B蛋白积累在洗涤剂不溶性的细胞质聚集体和酪氨酸磷酸化不足。与野生型DYRK1B相比，突变型DYRK1B变体更容易受到HSP 90抑制剂ganetespib的影响，并显示出与共伴侣CDC 37的结合增强。这些结果支持的假设，在DH盒中的突变干扰DYRK1B的成熟酪氨酸自磷酸化和妥协的催化结构域的构象稳定性，这使得激酶容易错误折叠。
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.
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DOI：
10.4161/cc.21404
发表时间：
2012-09-15
期刊：
Cell cycle (Georgetown, Tex.)
影响因子：
--
作者：
Becker W
通讯作者：
Becker W
影响因子：
4
作者：
Friedman, Eileen
通讯作者：
Friedman, Eileen
DOI：
10.1056/nejmoa1301824
发表时间：
2014-05-15
期刊：
The New England journal of medicine
影响因子：
--
作者：
Keramati AR;Fathzadeh M;Go GW;Singh R;Choi M;Faramarzi S;Mane S;Kasaei M;Sarajzadeh-Fard K;Hwa J;Kidd KK;Babaee Bigi MA;Malekzadeh R;Hosseinian A;Babaei M;Lifton RP;Mani A
通讯作者：
Mani A
影响因子：
4.1
作者：
Kinstrie, Ross;Lochhead, Pamela A.;Cleghon, Vaughn
通讯作者：
Cleghon, Vaughn
影响因子：
7.3
作者：
Kinstrie, Ross;Luebbering, Nathan;Cleghon, Vaughn
通讯作者：
Cleghon, Vaughn