ALPK3 Functions as a Pseudokinase.
ALPK3 Functions as a Pseudokinase.
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ALPK3 具有假激酶的功能。
DOI：
10.1161/circulationaha.123.065993
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发表时间：
2023
期刊：
影响因子：
37.8
通讯作者：
Chen,Ju
中科院分区：
文献类型：
--
作者：
Feng,Wei;Bogomolovas,Julius;Wang,Li;Li,Mengchen;Chen,Ju
ALPK3 属于 α-激酶家族，具有独特的结构特征和调节机制，使其有别于经典的真核蛋白激酶。最近的研究对 ALPK3 激酶活性提出了相互矛盾的发现。 2, 3 Agarwal 等人使用人类多能干细胞来源的心肌细胞进行了磷酸化蛋白质组学研究，比较了野生型 ALPK3、ALPK3 无效突变体和预计对其推定激酶活性至关重要的关键保守残基的 ALPK3 突变体。对于任何这些变体，在蛋白质组中均未观察到磷酸化的显着变化。此外，即使在 HEK293T 细胞中大量过度表达 ALPK3，整个蛋白质组中也没有检测到磷酸化的显着变化。因此，他们得出结论：ALPK3 不具有激酶活性。 2 然而，McNamara 等人报告称，当将重组 ALPK3 激酶结构域添加到 ALPK3 缺陷的人多能干细胞来源的心肌细胞的裂解物中时，磷酸化蛋白显着增加，并且 ALPK3 直接磷酸化 SQSTM1 的 T269/S272 位点。 3 值得注意的是，这两项研究都是通过测量培养细胞或体外的磷酸化事件来评估 ALPK3 的激酶活性。 ALPK3 是否作为心脏中真正的激酶发挥作用仍不清楚。
ALPK3 belongs to the α-kinase family, characterized by unique structural features and regulatory mechanisms that set them apart from canonical eukaryotic protein kinases. Recent studies present conflicting findings on ALPK3’s kinase activity. 2, 3 Agarwal et al performed phosphoproteomic studies using human pluripotent stem cell–derived cardiomyocytes, comparing wild-type ALPK3, ALPK3 null mutant, and ALPK3 mutants of key conserved residues predicted to be essential for its putative kinase activity. No significant changes in phosphorylation were observed across the proteome for any of these variants. In addition, even upon massive overexpression of ALPK3 in HEK293T cells, no significant alterations in phosphorylation were detected across the proteome. Thus, they concluded that ALPK3 does not have kinase activity. 2 However, McNamara et al reported a significant increase in phosphorylated proteins when the recombinant ALPK3 kinase domain is added to lysates from ALPK3-deficient human pluripotent stem cell–derived cardiomyocytes, and ALPK3 directly phosphorylates SQSTM1 at the T269/S272 site. 3 It is important to note that both studies assessed the kinase activity of ALPK3 by measuring phosphorylation events in cultured cells or in vitro. Whether ALPK3 functions as a true kinase in the heart remains unknown.