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

存在于生物体DNA中的基因编码特定蛋白质的产生。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。蛋白质修饰可以提高蛋白质的多样性，而不仅仅是在DNA水平上编码。例如，许多蛋白质通过脂肪酸棕榈酸酯的附着被修饰，这一过程被称为棕榈酰化。神经元（大脑中专门的细胞）之间的交流是每一个动作、思想和感觉的基础；这种神经元间的交流发生在称为突触的特殊部位。一些对神经元通讯至关重要的蛋白质棕榈酰化介导它们靶向突触；调节这种靶向的程度会影响突触通讯。众所周知，突触通讯的变化对学习和记忆等事件很重要。尽管棕榈酰化对正常突触功能很重要，但介导棕榈酰化反应的酶是如何在神经元中调节的，我们知之甚少。最近的研究发现了一个由24个DHHC蛋白组成的家族，这些蛋白基本上负责所有的细胞棕榈酰化活性。将这些蛋白的基因突变与精神分裂症和智力迟钝联系起来的研究，突出了DHHC蛋白对正常脑功能的重要性。DHHC2是脑内表达量最高的DHHC蛋白之一，本课题将重点研究DHHC2。此外，DHHC2靶向突触区域，在那里它可以使一种名为PSD95的蛋白质棕榈酰化；这种蛋白质在稳定神经递质受体方面起着重要作用，因此对突触通讯至关重要。DHHC2对PSD95的棕榈酰化导致PSD95的突触靶向性增加，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DHHC2向棕榈酰化PSD95的突触运动的调节机制。此外，我们将研究干扰DHHC2在突触上的移动如何影响神经元通讯。这项工作将在描述棕榈酰化动力学如何在突触中调节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。目前人们对DHHC蛋白作为治疗多种人类疾病的潜在药物靶点非常感兴趣，因此描述特定DHHC蛋白调节细胞动力学的机制非常重要。

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.