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Deciphering the molecular mechanism of HD-PTP function in endosomal trafficking

破译HD-PTP在内体运输中功能的分子机制

基本信息

批准号：
MR/K011049/1
负责人：
Lydia Tabernero
金额：
$ 59.63万
依托单位：
University of Manchester
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2013
资助国家：
英国
起止时间：
2013 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=MR%2FK011049%2F1
关键词：
Deciphering molecular mechanism HD PTP

项目摘要

The behaviour of cells within a tissue is controlled by their response to the environment. Receptor molecules at the cell surface receive a large number of chemical and physical stimuli that transmit signals to the interior of the cell and control important processes such cell migration, metabolism, cell proliferation and differentiation. Anomalies in the transmission of such signals result in pathological states that derive in diseases like cancer, diabetes, muscular dystrophy and neurological degeneration. Amongst the most important signals that cells receive are from circulating small proteins called growth factors. These bind to specialised receptors that alter their pattern of interactions with many molecules inside the cell to generate a mitogenic response and control cell growth. In order to prevent overstimulation of the cell response, there are mechanisms of regulation to ensure that these responses are not sustained endlessly, which would lead to uncontrolled cell division and proliferation. These mechanisms encompass the internalisation of the receptor upon stimulation leading it to specialised compartments or endosomes within the cell where they are ultimately destroyed. We discovered a key protein, HD-PTP, which controls this mechanism of receptor down-regulation and identified several specific biological partners within the endocytic pathway. The endocytic pathway is also critical in protecting against viral and bacterial infections and to eliminate protein aggregates that otherwise accumulate inside the cells and result in neurodegeneration observed in Alzheimer, Parkinson and Huntington diseases. Our main aim is to characterise these interactions at the molecular level to understand in detail the important mechanism of action of HD-PTP. The knowledge gained with these investigations will bring new insights into the molecular basis of many diseases caused by mutations in effectors of the endocytic pathway and in the long-term will guide further efforts for pharmacological intervention.

组织内细胞的行为由它们对环境的反应控制。细胞表面的受体分子接受大量的化学和物理刺激，将信号传递到细胞内部，控制细胞迁移、新陈代谢、细胞增殖和分化等重要过程。这种信号传输的异常会导致病理状态，这些状态源于癌症、糖尿病、肌肉营养不良和神经退化等疾病。细胞接收到的最重要的信号之一是来自循环中的称为生长因子的小蛋白。它们与特殊的受体结合，改变它们与细胞内许多分子相互作用的模式，以产生有丝分裂反应并控制细胞生长。为了防止过度刺激细胞反应，存在一种调节机制，以确保这些反应不会无休止地持续下去，从而导致细胞分裂和增殖失控。这些机制包括受体在刺激下的内化，导致它进入细胞内的特殊隔室或内小体，在那里它们最终被摧毁。我们发现了一种关键蛋白HD-PTP，它控制着这种受体下调的机制，并确定了内吞途径中的几个特定的生物伙伴。内吞途径在预防病毒和细菌感染以及消除蛋白质聚集方面也是至关重要的，否则蛋白质聚集在细胞内，并导致阿尔茨海默病、帕金森病和亨廷顿病中观察到的神经退化。我们的主要目的是在分子水平上表征这些相互作用，以详细了解HD-PTP的重要作用机制。通过这些研究获得的知识将为许多疾病的分子基础带来新的见解，这些疾病是由内吞途径的效应器突变引起的，从长远来看，将指导进一步的药物干预努力。

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

His domain protein tyrosine phosphatase and Rabaptin-5 couple endo-lysosomal sorting of EGFR with endosomal maturation.

DOI：
10.1242/jcs.259192
发表时间：
2021-11-01
期刊：
Journal of cell science
影响因子：
4
作者：
Parkinson G;Roboti P;Zhang L;Taylor S;Woodman P
通讯作者：
Woodman P

Crystallization of PTP Domains.

PTP 结构域的结晶。

DOI：
10.1007/978-1-4939-3746-2_10
发表时间：
2016
期刊：
Methods in molecular biology (Clifton, N.J.)
影响因子：
0
作者：
Levy C
通讯作者：
Levy C

The open architecture of HD-PTP phosphatase provides new insights into the mechanism of regulation of ESCRT function.

HD-PTP磷酸酶的开放结构为ESCRT功能调节机理提供了新的见解。

DOI：
10.1038/s41598-017-09467-9
发表时间：
2017-08-22
期刊：
Scientific reports
影响因子：
4.6
作者：
Gahloth D;Heaven G;Jowitt TA;Mould AP;Bella J;Baldock C;Woodman P;Tabernero L
通讯作者：
Tabernero L

Spin Labeling of Surface Cysteines Using a Bromoacrylaldehyde Spin Label.

DOI：
10.1007/s00723-021-01350-1
发表时间：
2021
期刊：
Applied magnetic resonance
影响因子：
1
作者：
Heaven G;Hollas MA;Tabernero L;Fielding AJ
通讯作者：
Fielding AJ

Structural Basis for Selective Interaction between the ESCRT Regulator HD-PTP and UBAP1.

DOI：
10.1016/j.str.2016.10.006
发表时间：
2016-12-06
期刊：
STRUCTURE
影响因子：
5.7
作者：
Gahloth, Deepankar;Levy, Colin;Heaven, Graham;Stefani, Flavia;Wunderley, Lydia;Mould, Paul;Cliff, Matthew J.;Bella, Jordi;Fielding, Alistair J.;Woodman, Philip;Tabernero, Lydia
通讯作者：
Tabernero, Lydia