Neurobeachin: A Protein Kinase A-Anchoring,beige/Chediak-Higashi Protein Homolog Implicated in Neuronal Membrane Traffic
Neurobeachin: A Protein Kinase A-Anchoring,beige/Chediak-Higashi Protein Homolog Implicated in Neuronal Membrane Traffic
复制标题
DOI：
10.1523/jneurosci.20-23-08551.2000
复制
发表时间：
2000-12
期刊：
影响因子：
--
通讯作者：
Xiaolu Wang;F. Herberg;M. Laue;C. Wüllner;Bin Hu;E. Petrasch‐Parwez;M. Kilimann
中科院分区：
文献类型：
--
作者：
Xiaolu Wang;F. Herberg;M. Laue;C. Wüllner;Bin Hu;E. Petrasch‐Parwez;M. Kilimann
我们描述的识别和初步表征的神经海滩蛋白，神经元特异性的多结构域蛋白的327 kDa的高亲和力结合位点（Kd，10 nm）的II型调节亚基的蛋白激酶A（PKA RII）。Neurobeachin是周边与多形性tubulovesicular内膜附近的transsides的高尔基体堆栈和整个细胞体和细胞过程。它也存在于突触的亚群中，集中在突触后质膜上。在活细胞中，核周神经海滩蛋白在1 min内被布雷菲德菌素A（BFA）分散，在透化细胞中，神经海滩蛋白从胞质到高尔基体附近的膜的募集被GTPγS刺激，并被布雷菲德菌素A阻止。神经海滩蛋白的募集点接近但不同于参与囊泡出芽的COP-I、AP-1和AP-3外壳蛋白的募集位点。这些观察结果表明，neurobeachin绑定到膜接近thetrans-高尔基体需要一个ADP-核糖基化因子样的GTdR，可能与一种新型的蛋白质外壳。一种不结合RII的神经海滩素同种型，即米色样蛋白（BGL），在许多组织中表达。Neurobeachin、BGL和其他哺乳动物基因产物共享一个特征性的C-末端BEACH-WD 40序列模块，该模块也存在于无脊椎动物、植物、原生动物和酵母的基因产物中，从而定义了一个新的蛋白质家族。这个海滩结构域蛋白家族的原型成员，溶酶体运输调节因子（LYST），在溶酶体生物发生中缺乏蛋白分选的遗传缺陷（米色小鼠和Chediak-Higashi综合征）。Neurobeachin的亚细胞定位，其外壳蛋白样膜招聘，其序列相似性LYST表明参与神经元后高尔基体膜交通，其功能之一是招募蛋白激酶A的膜与它相关联。
We describe the identification and initial characterization of neurobeachin, a neuron-specific multidomain protein of 327 kDa with a high-affinity binding site (Kd, 10 nm) for the type II regulatory subunit of protein kinase A (PKA RII). Neurobeachin is peripherally associated with pleomorphic tubulovesicular endomembranes near the transsides of Golgi stacks and throughout the cell body and cell processes. It is also found in a subpopulation of synapses, where it is concentrated at the postsynaptic plasma membrane. In live cells, perinuclear neurobeachin is dispersed by brefeldin A (BFA) within 1 min, and in permeabilized cells a recruitment of neurobeachin from cytosol to Golgi-near membranes is stimulated by GTPγS and prevented by brefeldin A. Spots of neurobeachin recruitment are close to but distinct from recruitment sites of COP-I, AP-1, and AP-3 coat proteins involved in vesicle budding. These observations indicate that neurobeachin binding to membranes close to thetrans-Golgi requires an ADP-ribosylation factor-like GTPase, possibly in association with a novel type of protein coat. A neurobeachin isoform that does not bind RII, beige-like protein (BGL), is expressed in many tissues. Neurobeachin, BGL, and ∼10 other mammalian gene products share a characteristic C-terminal BEACH-WD40 sequence module, which is also present in gene products of invertebrates, plants, protozoans, and yeasts, thus defining a new protein family. The prototype member of this family of BEACH domain proteins, lysosomal trafficking regulator (LYST), is deficient in genetic defects of protein sorting in lysosome biogenesis (thebeige mouse and Chediak-Higashi syndrome). Neurobeachin's subcellular localization, its coat protein-like membrane recruitment, and its sequence similarity to LYST suggest an involvement in neuronal post-Golgi membrane traffic, one of its functions being to recruit protein kinase A to the membranes with which it associates.