Janes Peter W, Saha Nayanendu, Barton William A, Kolev Momchil V, Wimmer-Kleikamp Sabine H, Nievergall Eva, Blobel Carl P, Himanen Juha-Pekka, Lackmann Martin, Nikolov Dimitar B
Department of Biochemistry and Molecular Biology, PO Box 13D, Monash University, Victoria 3800, Australia.
Cell. 2005 Oct 21;123(2):291-304. doi: 10.1016/j.cell.2005.08.014.
The Eph family of receptor tyrosine kinases and their ephrin ligands are mediators of cell-cell communication. Cleavage of ephrin-A2 by the ADAM10 membrane metalloprotease enables contact repulsion between Eph- and ephrin-expressing cells. How ADAM10 interacts with ephrins in a regulated manner to cleave only Eph bound ephrin molecules remains unclear. The structure of ADAM10 disintegrin and cysteine-rich domains and the functional studies presented here define an essential substrate-recognition module for functional interaction of ADAM10 with the ephrin-A5/EphA3 complex. While ADAM10 constitutively associates with EphA3, the formation of a functional EphA3/ephrin-A5 complex creates a new molecular recognition motif for the ADAM10 cysteine-rich domain that positions the proteinase domain for effective ephrin-A5 cleavage. Surprisingly, the cleavage occurs in trans, with ADAM10 and its substrate being on the membranes of opposing cells. Our data suggest a simple mechanism for regulating ADAM10-mediated ephrin proteolysis, which ensures that only Eph bound ephrins are recognized and cleaved.
受体酪氨酸激酶的Eph家族及其ephrin配体是细胞间通讯的介质。ADAM10膜金属蛋白酶对ephrin-A2的切割使得表达Eph和ephrin的细胞之间产生接触排斥。ADAM10如何以一种受调控的方式与ephrins相互作用，从而仅切割与Eph结合的ephrin分子，目前尚不清楚。本文所展示的ADAM10解整合素和富含半胱氨酸结构域的结构以及功能研究，确定了一个ADAM10与ephrin-A5/EphA3复合体进行功能相互作用的重要底物识别模块。虽然ADAM10与EphA3组成性结合，但功能性EphA3/ephrin-A5复合体的形成，为ADAM10富含半胱氨酸的结构域创造了一个新的分子识别基序，将蛋白酶结构域定位以有效地切割ephrin-A5。令人惊讶的是，切割发生在反式中，ADAM10及其底物位于相对细胞的膜上。我们的数据提示了一种调节ADAM10介导的ephrin蛋白水解的简单机制，该机制确保只有与Eph结合的ephrins被识别和切割。
