The Hedgehog receptors PTCH1 and PTCH2 exist as active homomeric and heteromeric complexes
The Hedgehog receptors PTCH1 and PTCH2 exist as active homomeric and heteromeric complexes
复制标题
Hedgehog 受体 PTCH1 和 PTCH2 作为活性同聚和异聚复合物存在
DOI：
10.1101/2023.08.08.549832
复制
发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Timmis A
中科院分区：
文献类型：
--
作者：
Timmis A
由于Hedgehog信号在胚胎发育、组织稳态和疾病中的重要性，了解信号转导的分子机制对于设计特异性、有效的治疗方法至关重要。刺猬受体PTCH 1和较少研究的PTCH 2亚型在进化上与细菌RND渗透酶和甾醇传感蛋白相关，其通过阳离子梯度动员疏水化合物。在这里，我们表明，在活跃状态下，PTCH 1和PTCH 2形成的同源和异源复合物，抑制结合的音速刺猬。我们发现，PTCH 2，不像PTCH 1，似乎有最小的胆固醇转运活性，但保守的残基参与阳离子转运是必不可少的，其功能。异聚PTCH 1-PTCH 2复合物依赖于PTCH 1的胆固醇转运能力，但阳离子转运可以由PTCH 2反式提供，这表明在任一同种型中的一些有害突变可以通过形成异聚体而沉默，从而增强该信号转导系统的稳健性。这些发现为PTCH 2的有趣行为提供了分子基础，PTCH 2在功能上与PTCH 1半冗余和部分重叠，并解释了在罕见的癌症病例中破坏PTCH 2阳离子转运三联体的突变的显性负效应。
With the importance of Hedgehog signalling in embryonic development, tissue homeostasis and disease, understanding the molecular mechanisms of signal transduction is paramount for the design of specific, effective therapeutics. The Hedgehog receptor PTCH1 and the less studied PTCH2 isoform are evolutionarily related to bacterial RND permeases and sterol sensing proteins, which mobilise hydrophobic compounds powered by a cation gradient. Here we demonstrate that, in the active state, PTCH1 and PTCH2 form homomeric and heteromeric complexes that are inhibited by binding of Sonic Hedgehog. We show that PTCH2, unlike PTCH1, appears to have minimal cholesterol transport activity, but that conserved residues involved in cation transport are essential for its function. Heteromeric PTCH1-PTCH2 complexes depend on PTCH1’s cholesterol transport capacity, but the cation transport can be provided in trans by PTCH2, suggesting that some deleterious mutations in either isoform can be silenced by formation of heteromers, enhancing the robustness of this signal transduction system. These findings provide the molecular basis for the intriguing behaviour of PTCH2 as semi-redundant and partially overlapping in function with PTCH1 and explain the dominant negative effect of mutations that disrupt the PTCH2 cation transport triad in rare cases of cancer.
登录
查看更多内容
影响因子：
11.2
作者：
Lee, Youngsoo;Miller, Heather L.;McKinnon, Peter J.
通讯作者：
McKinnon, Peter J.
影响因子：
62.1
作者：
Klenotic PA;Moseng MA;Morgan CE;Yu EW
通讯作者：
Yu EW
尼曼-皮克 C1 蛋白
DOI：
10.1002/0471203076.emm0453
发表时间：
2002
期刊：
American journal of physiology. Renal physiology
影响因子：
--
作者：
Y. Ioannou
通讯作者：
Y. Ioannou
DOI：
10.1016/j.bbapap.2008.10.004
发表时间：
2009-05
期刊：
Biochimica et biophysica acta
影响因子：
--
作者：
Nikaido H;Takatsuka Y
通讯作者：
Takatsuka Y
DOI：
10.1073/pnas.0405255101
发表时间：
2004-08-24
影响因子：
11.1
作者：
Ohgami, N;Ko, DC;Chang, TY
通讯作者：
Chang, TY