Collagen binding specificity of the discoidin domain receptors: binding sites on collagens II and III and molecular determinants for collagen IV recognition by DDR1.
Collagen binding specificity of the discoidin domain receptors: binding sites on collagens II and III and molecular determinants for collagen IV recognition by DDR1.
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DOI：
10.1016/j.matbio.2010.10.004
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发表时间：
2011-01
期刊：
影响因子：
6.9
通讯作者：
Leitinger, Birgit
中科院分区：
文献类型：
--
作者：
Xu, Huifang;Raynal, Nicolas;Stathopoulos, Stavros;Myllyharju, Johanna;Farndale, Richard W.;Leitinger, Birgit
关键词：
盘状结构域受体DDR 1和DDR2是由三螺旋胶原激活的细胞表面受体酪氨酸激酶。虽然正常的DDR信号调节基本的细胞过程，但异常的DDR信号与几种人类疾病有关。我们以前确定GVMGFO（O是羟脯氨酸）作为一个主要的DDR2结合位点的胶原蛋白I-III，并定位两个额外的DDR2结合位点的胶原蛋白II。在这里，我们将这些研究扩展到同源DDR 1和胶原蛋白III上的DDR结合位点的鉴定。使用重叠的三螺旋肽组，胶原蛋白II和胶原蛋白III工具包，我们在两种胶原蛋白上定位了几个DDR2结合位点。DDR 1与Toolkit肽的相互作用更受限制，DDR 1主要与含有GVMGFO基序的肽结合。含有GVMGFO基序的三螺旋肽诱导DDR 1跨膜信号传导，并且DDR 1结合和受体活化发生与先前针对DDR2定义的相同氨基酸要求。虽然两种DDR表现出相同的特异性结合GVMGFO基序，这是只存在于纤维状胶原蛋白，这两种受体显示出不同的偏好，某些非纤维状胶原蛋白，与基膜胶原蛋白IV是排他性识别的DDR 1。基于我们最近的晶体结构的DDR2-胶原蛋白复合物，我们设计的突变，以确定DDR 1结合胶原蛋白IV的分子决定因素。通过用相应的DDR 1残基替换DDR2中的五个氨基酸，我们能够创建可以作为胶原IV受体起作用的DDR2构建体。
The discoidin domain receptors, DDR1 and DDR2 are cell surface receptor tyrosine kinases that are activated by triple-helical collagen. While normal DDR signalling regulates fundamental cellular processes, aberrant DDR signalling is associated with several human diseases. We previously identified GVMGFO (O is hydroxyproline) as a major DDR2 binding site in collagens I–III, and located two additional DDR2 binding sites in collagen II. Here we extend these studies to the homologous DDR1 and the identification of DDR binding sites on collagen III. Using sets of overlapping triple-helical peptides, the Collagen II and Collagen III Toolkits, we located several DDR2 binding sites on both collagens. The interaction of DDR1 with Toolkit peptides was more restricted, with DDR1 mainly binding to peptides containing the GVMGFO motif. Triple-helical peptides containing the GVMGFO motif induced DDR1 transmembrane signalling, and DDR1 binding and receptor activation occurred with the same amino acid requirements as previously defined for DDR2. While both DDRs exhibit the same specificity for binding the GVMGFO motif, which is present only in fibrillar collagens, the two receptors display distinct preferences for certain non-fibrillar collagens, with the basement membrane collagen IV being exclusively recognised by DDR1. Based on our recent crystal structure of a DDR2-collagen complex, we designed mutations to identify the molecular determinants for DDR1 binding to collagen IV. By replacing five amino acids in DDR2 with the corresponding DDR1 residues we were able to create a DDR2 construct that could function as a collagen IV receptor.
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影响因子：
20.3
作者：
Jarvis GE;Raynal N;Langford JP;Onley DJ;Andrews A;Smethurst PA;Farndale RW
通讯作者：
Farndale RW
DOI：
10.1016/j.str.2009.10.012
发表时间：
2009-12-09
期刊：
Structure (London, England : 1993)
影响因子：
--
作者：
Carafoli F;Bihan D;Stathopoulos S;Konitsiotis AD;Kvansakul M;Farndale RW;Leitinger B;Hohenester E
通讯作者：
Hohenester E
影响因子：
9.8
作者：
Bargal, Ruth;Cormier-Daire, Valerie;Raas-Rothschild, Annick
通讯作者：
Raas-Rothschild, Annick
影响因子：
64.5
作者：
Emsley, J;Knight, CG;Liddington, RC
通讯作者：
Liddington, RC
影响因子：
4.8
作者：
Leitinger, B
通讯作者：
Leitinger, B