MOLECULAR MECHANISMS OF THE ELP COMPLEX AND ASSOCIATED FACTORS

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 我们的实验室长期以来一直对了解Rab蛋白在膜运输中激活的分子事件感兴趣，最近我们通过遗传筛选分离了IKAP的酵母同源物Elp1p，以确定调控Rab GTPase作用的因素。FD综合征蛋白在与其他五种蛋白的复合体中被发现，称为Elongator复合体。我们的研究揭示了ELP复合体在调节极化胞吐作用中的重要细胞质作用[1]。人类ELP1基因突变是导致家族性自主神经障碍的原因之一。这项研究的长期目标是阐明FD疾病综合征蛋白的机制以及从IKAP失调到临床症状的途径。 该项目旨在了解Elp1p和Elongator复合体调节极化分泌和生长的分子机制。为了确定在ELP途径中起作用的其他基因和蛋白质，我们进行了额外的遗传筛选，从而确定了一种蛋白质，该蛋白质是通过翻译后修饰改变生长控制蛋白质的潜在靶点。结合Elp3p的乙酰化活性鉴定靶标和修饰实体将有助于我们理解调控极化分泌和细胞生长的分子机制。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Our lab has had a long-standing interest in understanding the molecular events underlying the activation of Rab proteins in membrane traffic, and we recently isolated the yeast homolog of IKAP, Elp1p, via a genetic screen to identify factors regulating Rab GTPase action. The FD syndrome protein is found in a complex with five other proteins, termed the Elongator complex. Our studies revealed an essential cytoplasmic role for the Elp complex in the regulation of polarized exocytosis [1]. Mutations in the human ELP1 gene are a cause of the neurological disorder Familial Dysautonomia. The long-term goal of the research is to elucidate the mechanism of the FD disease syndrome protein and the pathway leading from IKAP dysregulation to the clinical symptoms. The project proposed here is directed at understanding the molecular mechanisms by which Elp1p and the Elongator complex regulate polarized secretion and growth. To identify other genes and proteins that act in the Elp pathway we have conducted additional genetic screens that have resulted in the identification of a protein that is a potential target for altering growth control proteins via post-translational modification. Identification of the targets and modified entities in conjunction with the acetylation activities of Elp3p will help us understand the molecular mechanisms that regulate polarized secretion and cell growth.