Department of Pharmacology, University of Washington, Seattle, WA 98195, USA.
Sci Signal. 2023 Jan 3;16(766):eadd3269. doi: 10.1126/scisignal.add3269.
Mutations in , which encodes a serine-threonine kinase, are associated with both autism spectrum disorder (ASD) and neurodevelopmental delay (NDD). Here, we investigated the molecular function of this evolutionarily conserved kinase and the mechanisms through which mutations may lead to neuropathology. We found that TAOK1 was abundant in neurons in the mammalian brain and remodeled the neuronal plasma membrane through direct association with phosphoinositides. Our characterization of four NDD-associated mutations revealed that these mutants were catalytically inactive and were aberrantly trapped in a membrane-bound state, which induced abnormal membrane protrusions. Expression of these TAOK1 mutants in cultured mouse hippocampal neurons led to abnormal growth of the dendritic arbor. The coiled-coil region carboxyl-terminal to the kinase domain was predicted to fold into a triple helix, and this region directly bound phospholipids and was required for both membrane association and induction of aberrant protrusions. Autophosphorylation of threonine-440 and threonine-443 in the triple-helical region by the kinase domain blocked the plasma membrane association of TAOK1. These findings define TAOK1 as a plasma membrane remodeling kinase and reveal the underlying mechanisms through which TAOK1 dysfunction may lead to neurodevelopmental disorders.
编码丝氨酸-苏氨酸激酶的 突变与自闭症谱系障碍（ASD）和神经发育迟缓（NDD）有关。在这里，我们研究了这种进化上保守的激酶的分子功能，以及 突变导致神经病理学的机制。我们发现 TAOK1 在哺乳动物大脑中的神经元中含量丰富，并通过与磷酸肌醇直接结合来重塑神经元质膜。我们对四个与 NDD 相关的 突变的特征描述表明，这些突变体无催化活性，并且异常被困在膜结合状态，从而诱导异常的膜突。在培养的小鼠海马神经元中表达这些 TAOK1 突变体导致树突分支的异常生长。预测激酶结构域羧基末端的卷曲螺旋区域会折叠成三螺旋，该区域直接与磷脂结合，是膜结合和诱导异常突起所必需的。激酶结构域对三螺旋区域中的苏氨酸-440 和苏氨酸-443 的自身磷酸化阻止了 TAOK1 与质膜的结合。这些发现将 TAOK1 定义为一种质膜重塑激酶，并揭示了 TAOK1 功能障碍导致神经发育障碍的潜在机制。
