Molecular dissection of DHHC protein targeting and its importance for post-synaptic palmitoylation dynamics

生物体DNA中存在的基因编码产生特定的蛋白质。在单个细胞内产生的数千种蛋白质相互作用，驱动多种途径，如细胞生长和分裂。蛋白质修饰可以增强蛋白质的多样性，而不是DNA水平上的编码。例如，许多蛋白质被脂肪酸棕榈酸酯的附着所修饰，这一过程被称为棕榈酰化。神经元之间的通信是大脑中每一种运动、思想和感觉的基础；这种神经元通信发生在称为突触的特殊位置。几种对神经元通讯至关重要的蛋白质的棕榈酰化调节了它们对突触的靶向；调节这种靶向的程度会影响突触通讯。众所周知，突触交流的变化对学习和记忆等事件很重要。尽管棕榈酰化对于正常的突触功能很重要，但人们对介导棕榈酰化反应的酶是如何在神经元中进行调控的知之甚少。最近的工作确定了一个24个‘DHHC’蛋白家族，它们基本上负责细胞的所有棕榈酰化活性。通过将这些蛋白的基因突变与精神分裂症和智力低下联系起来，DHHC蛋白对正常大脑功能的重要性得到了突显。本研究项目将专注于DHHC2，它是大脑中表达最高的DHHC蛋白之一。此外，DHHC2的靶点是突触区域，在那里它被证明能棕榈酰化一种名为PSD95的蛋白质；这种蛋白质在稳定神经递质受体方面发挥着重要作用，因此对突触通信是必不可少的。DHHC2对PSD95的棕榈酰化导致PSD95突触靶向性增加，进而影响神经递质受体的突触动力学。在这个项目中，我们将研究调节DHHC2向突触移动的机制，在那里它棕榈酰化PSD95。此外，我们将研究干扰DHHC2在突触上的移动性如何影响神经元通信。这项工作将在阐明突触棕榈酰化动力学是如何调节的以及这种调节对神经递质受体动力学的下游影响方面发挥重要作用。目前，DHHC蛋白作为治疗多种人类疾病的潜在药物靶点受到了极大的关注，从而阐明特定的DHHC蛋白调节细胞动力学的机制具有重要意义。

Genes present within the DNA of living organisms encode for the production of specific proteins. The thousands of proteins that are produced within a single cell interact to drive a multitude of pathways, such as cell growth and division. Protein modifications can enhance protein diversity beyond that encoded at the DNA level. For example, many proteins are modified by the attachment of the fatty acid palmitate, a process termed palmitoylation.Communication between neurons, specialised cells in the brain, underlies every movement, thought and sensation; this neuronal communication occurs at specialised sites termed synapses. Palmitoylation of several proteins that are essential for neuronal communication mediates their targeting to synapses; modulating the extent of this targeting affects synaptic communication. It is well established that changes in synaptic communication are important for events such as learning and memory. Despite the importance of palmitoylation for normal synaptic function, there is very little known about how the enzymes that mediate palmitoylation reactions are regulated in neurons. Recent work identified a family of 24 'DHHC' proteins that are responsible for essentially all cellular palmitoylation activity. The importance of DHHC proteins for normal brain function is highlighted by work linking genetic mutations in these proteins with schizophrenia and mental retardation.This research project will focus on DHHC2, which is one of the most highly expressed DHHC proteins in brain. Furthermore, DHHC2 is targeted to synaptic regions, where it has been shown to palmitoylate a protein called PSD95; this protein plays an important role in stabilising neurotransmitter receptors and is therefore essential for synaptic communication. Palmitoylation of PSD95 by DHHC2 leads to an increase in synaptic targeting of PSD95, which in turn affects synaptic dynamics of neurotransmitter receptors. In this project, we will investigate the mechanisms that regulate DHHC2 movement to synapses where it palmitoylates PSD95. Furthermore, we will examine how interfering with the mobility of DHHC2 at synapses impacts neuronal communication. This work will play a major role in delineating how palmitoylation dynamics are regulated at synapses and the downstream effects of this regulation on neurotransmitter receptor dynamics.There is currently much interest in DHHC proteins as potential drug targets for the treatment of diverse human disorders, thus delineating the mechanisms whereby specific DHHC proteins regulate cellular dynamics is of major importance.