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Discoidin domain receptor signalling: from crystal structures to mechanisms

盘状蛋白结构域受体信号传导：从晶体结构到机制

基本信息

批准号：
BB/I011226/1
负责人：
Birgit Leitinger
金额：
$ 44.77万
依托单位：
Imperial College London
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2011
资助国家：
英国
起止时间：
2011 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=BB%2FI011226%2F1
关键词：
Discoidin domain receptor signalling crystal

项目摘要

We want to find out how specialised sensor proteins on the cell surface, called DDRs, transmit a signal into the cell. This research is important because faulty DDR signalling in humans can cause disease, for example arthritis and cancer. In order to develop drugs that target the DDRs, it is necessary to know the structure and understand the signalling mechanism of the DDRs. Our research will contribute towards this aim. The DDRs are composed of three parts: one part sticks out of the cell, a second part is embedded in the cell membrane, and a third part faces the interior of the cell. Previous studies have established that the DDRs are sensing the presence of collagen, which is a major constituent of all connective tissues. This allows cells to react to their environment. When collagen binds to the exterior part of DDRs, the interior part becomes active and informs the cell that collagen has been recognised. We do not understand what happens during this process, but we believe that the DDRs change their shape when they react with collagen. We will use a range of experimental techniques to study how DDRs bind collagen and how they respond to collagen binding. Collagen is difficult to study because it is a very large molecule. In our experiments we will use collagen peptides, which are small synthetic fragments of collagen. We have found that some collagen peptides can stimulate DDR activity, whereas others block DDR activity. Our previous experiments have revealed how DDR recognises a stimulatory collagen peptide. We now want to see how a blocking peptide is recognised. By comparing the DDR structures obtained with stimulatory and blocking peptides, we hope to learn more about the shape changes that occur during signal transmission. Our previous experiments have also revealed that the whole exterior part of DDRs pairs with itself to form what is called a dimer. We will make small, precise changes in the DDR dimer and study their effects on signalling. By combining many such observations, we can construct a detailed map of the regions within the DDR molecule that are involved in transmitting a signal across the cell membrane. Finally, we have created a very useful tool for studying DDR function: a set of antibodies directed against DDR1 (DDR1 is one of the two DDRs in humans). Antibodies are normally made by animals as a defence against pathogens, but by injecting mice with DDR1 protein, we have been able to obtain antibodies that bind to DDR1. Some of these antibodies block DDR1 signalling, whereas others stimulate this activity even in the absence of collagen. In order to understand how these antibodies influence DDR1 activity, we want to determine where on the DDR1 molecule they bind. This information will complement our map of functionally important regions within the DDR1 molecule. We also plan to create antibodies against the second human DDR, DDR2. Our antibodies will be extremely useful research tools that can be shared with other researchers. They could also be used for diagnostic or therapeutic purposes, but the development of such reagents would have to be carried out in a pharmaceutical company.

我们想知道细胞表面上的专门传感器蛋白（称为DDRs）如何将信号传输到细胞中。这项研究很重要，因为人类错误的DDR信号可能导致疾病，例如关节炎和癌症。为了开发靶向DDRs的药物，有必要了解DDRs的结构并了解其信号传导机制。我们的研究将有助于实现这一目标。DDR由三部分组成：一部分伸出细胞外，第二部分嵌入细胞膜中，第三部分面向细胞内部。以前的研究已经确定，DDR可以感知胶原蛋白的存在，胶原蛋白是所有结缔组织的主要成分。这使得细胞能够对环境做出反应。当胶原蛋白与DDR的外部结合时，内部部分变得活跃并通知细胞胶原蛋白已被识别。我们不知道在这个过程中发生了什么，但我们相信当它们与胶原蛋白反应时，DDR会改变它们的形状。我们将使用一系列实验技术来研究DDRs如何结合胶原蛋白以及它们如何响应胶原蛋白结合。胶原蛋白很难研究，因为它是一个非常大的分子。在我们的实验中，我们将使用胶原蛋白肽，这是胶原蛋白的小合成片段。我们已经发现，一些胶原蛋白肽可以刺激DDR活性，而另一些则阻断DDR活性。我们之前的实验已经揭示了DDR如何识别刺激性胶原肽。我们现在想知道阻断肽是如何被识别的。通过比较刺激肽和阻断肽获得的DDR结构，我们希望更多地了解信号传递过程中发生的形状变化。我们之前的实验也揭示了DDRs的整个外部部分与自身配对形成所谓的二聚体。我们将在DDR二聚体中进行微小而精确的改变，并研究它们对信号传导的影响。通过结合许多这样的观察，我们可以构建DDR分子内参与跨细胞膜传递信号的区域的详细地图。最后，我们创造了一个非常有用的工具来研究DDR功能：一组针对DDR1的抗体（DDR1是人类两种DDR之一）。抗体通常由动物产生，作为对病原体的防御，但通过向小鼠注射DDR1蛋白，我们已经能够获得与DDR1结合的抗体。这些抗体中的一些阻断DDR1信号传导，而另一些即使在没有胶原蛋白的情况下也刺激这种活性。为了了解这些抗体如何影响DDR1活性，我们希望确定它们在DDR1分子上的结合位置。这些信息将补充我们的DDR1分子内功能重要区域的图谱。我们还计划制造针对第二种人类DDR，DDR2的抗体。我们的抗体将是非常有用的研究工具，可以与其他研究人员共享。它们还可以用于诊断或治疗目的，但此类试剂的开发必须在制药公司进行。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Discoidin domain receptor tyrosine kinases: new players in cancer progression.

DOI：
10.1007/s10555-012-9346-z
发表时间：
2012-06
期刊：
CANCER AND METASTASIS REVIEWS
影响因子：
9.2
作者：
Valiathan, Rajeshwari R.;Marco, Marta;Leitinger, Birgit;Kleer, Celina G.;Fridman, Rafael
通讯作者：
Fridman, Rafael

Analysis of Collagen-Binding Integrin Interactions with Supramolecular Aggregates of the Extracellular Matrix.

DOI：
10.1007/978-1-4939-9095-5_12
发表时间：
2019
期刊：
Methods in molecular biology
影响因子：
0
作者：
U. Hansen
通讯作者：
U. Hansen

Phosphoproteomics of collagen receptor networks reveals SHP-2 phosphorylation downstream of wild-type DDR2 and its lung cancer mutants.

DOI：
10.1042/bj20121750
发表时间：
2013-09-15
期刊：
The Biochemical journal
影响因子：
0
作者：
Iwai LK;Payne LS;Luczynski MT;Chang F;Xu H;Clinton RW;Paul A;Esposito EA;Gridley S;Leitinger B;Naegle KM;Huang PH
通讯作者：
Huang PH

Recombinant Collagen Engineered to Bind to Discoidin Domain Receptor Functions as a Receptor Inhibitor.

DOI：
10.1074/jbc.m115.674507
发表时间：
2016-02-26
期刊：
The Journal of biological chemistry
影响因子：
0
作者：
An B;Abbonante V;Xu H;Gavriilidou D;Yoshizumi A;Bihan D;Farndale RW;Kaplan DL;Balduini A;Leitinger B;Brodsky B
通讯作者：
Brodsky B

Discoidin domain receptor functions in physiological and pathological conditions.