Structure of mouse protocadherin 15 of the stereocilia tip link in complex with LHFPL5.
Structure of mouse protocadherin 15 of the stereocilia tip link in complex with LHFPL5.
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DOI：
10.7554/elife.38770
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发表时间：
2018-08-02
期刊：
影响因子：
7.7
通讯作者：
Gouaux E
中科院分区：
文献类型：
--
作者：
Ge J;Elferich J;Goehring A;Zhao H;Schuck P;Gouaux E
听觉和平衡涉及通过由原钙粘蛋白15（PCDH 15）和钙粘蛋白23“尖端连接”连接在一起的静纤毛束的偏转将机械刺激转换成电信号。PCDH 15将尖端连接张力转换为机械-电转换（MET）离子通道的打开。PCDH 15还与MET通道的候选亚基LHFPL 5相互作用。在这里，我们阐明了PCDH 15-LHFPL 5的结构，显示复合物是如何组成的PCDH 15和LHFPL 5亚基对相关的2倍轴。细胞外钙粘蛋白结构域定义了一个移动的系链，该系链与膜双层近端的刚性2重对称“领”偶联。LHFPL 5与PCDH 15跨膜螺旋形成广泛的相互作用，并稳定整个PCDH 15-LHFPL 5组装。我们的研究阐明了PCDH 15-LHFPL 5复合物的结构，定位与耳聋相关的突变，并揭示了PCDH 15系链中的力如何被转导到静纤毛膜中。
Hearing and balance involve the transduction of mechanical stimuli into electrical signals by deflection of bundles of stereocilia linked together by protocadherin 15 (PCDH15) and cadherin 23 ‘tip links’. PCDH15 transduces tip link tension into opening of a mechano-electrical transduction (MET) ion channel. PCDH15 also interacts with LHFPL5, a candidate subunit of the MET channel. Here we illuminate the PCDH15-LHFPL5 structure, showing how the complex is composed of PCDH15 and LHFPL5 subunit pairs related by a 2-fold axis. The extracellular cadherin domains define a mobile tether coupled to a rigid, 2-fold symmetric ‘collar’ proximal to the membrane bilayer. LHFPL5 forms extensive interactions with the PCDH15 transmembrane helices and stabilizes the overall PCDH15-LHFPL5 assembly. Our studies illuminate the architecture of the PCDH15-LHFPL5 complex, localize mutations associated with deafness, and shed new light on how forces in the PCDH15 tether may be transduced into the stereocilia membrane.