Department of Neuroscience and Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Hunterian 1001, 725 N. Wolfe Street, Baltimore, MD 21205, USA.
Neuron. 2012 Feb 9;73(3):482-96. doi: 10.1016/j.neuron.2011.11.021.
Palmitoylation, a key regulatory mechanism controlling protein targeting, is catalyzed by DHHC-family palmitoyl acyltransferases (PATs). Impaired PAT activity is linked to neurodevelopmental and neuropsychiatric disorders, suggesting critical roles for palmitoylation in neuronal function. However, few substrates for specific PATs are known, and functional consequences of palmitoylation events are frequently uncharacterized. Here, we identify the closely related PATs DHHC5 and DHHC8 as specific regulators of the PDZ domain protein GRIP1b. Binding, palmitoylation, and dendritic targeting of GRIP1b require a PDZ ligand unique to DHHC5/8. Palmitoylated GRIP1b is targeted to trafficking endosomes and may link endosomes to kinesin motors. Consistent with this trafficking role, GRIP1b's palmitoylation turnover rate approaches the highest of all reported proteins, and palmitoylation increases GRIP1b's ability to accelerate AMPA-R recycling. To our knowledge, these findings identify the first neuronal DHHC5/8 substrate, define novel mechanisms controlling palmitoylation specificity, and suggest further links between dysregulated palmitoylation and neuropathological conditions.
棕榈酰化作用是一种控制蛋白质靶向的关键调节机制，由 DHHC 家族棕榈酰转移酶（PATs）催化。PAT 活性受损与神经发育和神经精神疾病有关，表明棕榈酰化在神经元功能中具有关键作用。然而，已知的特定 PAT 底物很少，并且棕榈酰化事件的功能后果通常不明确。在这里，我们确定密切相关的 PATs DHHC5 和 DHHC8 是 PDZ 结构域蛋白 GRIP1b 的特定调节剂。GRIP1b 的结合、棕榈酰化和树突状靶向需要 DHHC5/8 特有的 PDZ 配体。棕榈酰化的 GRIP1b 被靶向到运输内体，并且可能将内体与驱动蛋白马达连接起来。与这种运输作用一致，GRIP1b 的棕榈酰化周转率接近所有报道的蛋白质中最高的，并且棕榈酰化增加了 GRIP1b 加速 AMPA-R 回收的能力。据我们所知，这些发现确定了第一个神经元 DHHC5/8 底物，定义了控制棕榈酰化特异性的新机制，并进一步提示失调的棕榈酰化与神经病理学状况之间的联系。
