The cryo-electron microscopy structure of huntingtin.
The cryo-electron microscopy structure of huntingtin.
复制标题
DOI：
10.1038/nature25502
复制
发表时间：
2018-03-01
期刊：
影响因子：
64.8
通讯作者：
Kochanek S
中科院分区：
文献类型：
--
作者：
Guo Q;Bin Huang;Cheng J;Seefelder M;Engler T;Pfeifer G;Oeckl P;Otto M;Moser F;Maurer M;Pautsch A;Baumeister W;Fernández-Busnadiego R;Kochanek S
亨廷顿蛋白（Huntingtin，Htt）是一种分子量为348 kDa的蛋白质，在胚胎发育过程中起重要作用，参与多种细胞活动，如囊泡转运、内吞、自噬和转录调控等。虽然缺乏对Htt生物学功能的综合理解，但大量鉴定的相互作用物表明Htt作为蛋白质-蛋白质相互作用中心。此外，亨廷顿氏病是由Htt基因中的突变引起的，该突变导致Htt的N-末端处的多聚谷氨酰胺（polyQ）重复的致病性扩增。然而，目前只有有限的结构信息Htt。在这里，我们采用冷冻电子显微镜（cryo-EM），以确定全长人Htt的结构与HAP 40/F8 A的复杂性，以4 μ m的分辨率。Htt主要是α-螺旋，由三个主要结构域组成。N-和C-末端结构域含有以螺线管方式排列的多个HEAT重复序列。这些结构域通过含有不同类型串联重复的较小桥结构域连接。HAP 40也主要是α-螺旋的，并且具有四肽重复（TPR）样组织。HAP 40通过疏水和静电相互作用结合在与三个Htt结构域接触的裂缝中，从而稳定Htt构象。这些数据使以前的生化结果合理化，并为更好地理解Htt的多种细胞功能铺平了道路。
Huntingtin (Htt) is a large (348 kDa) protein, essential for embryonic development and involved in diverse cellular activities such as vesicular transport, endocytosis, autophagy and transcription regulation. While an integrative understanding of Htt's biological functions is lacking, the large number of identified interactors suggests that Htt serves as a protein-protein interaction hub. Furthermore, Huntington’s disease is caused by a mutation in the Htt gene, resulting in a pathogenic expansion of a polyglutamine (polyQ) repeat at the N-terminus of Htt. However, only limited structural information on Htt is currently available. Here we employed cryo-electron microscopy (cryo-EM) to determine the structure of full-length human Htt in a complex with HAP40/F8A to 4 Å resolution. Htt is largely α-helical and consists of three major domains. The N- and C-terminal domains contain multiple HEAT repeats arranged in a solenoid fashion. These domains are connected by a smaller bridge domain containing different types of tandem repeats. HAP40 is also largely α-helical and has a tetratricopeptide repeat (TPR)-like organization. HAP40 binds in a cleft contacting the three Htt domains by hydrophobic and electrostatic interactions, thereby stabilizing Htt conformation. These data rationalize previous biochemical results and pave the way for an improved understanding of Htt’s diverse cellular functions.
登录
查看更多内容
DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K
影响因子：
11.4
作者：
El-Daher, Marie-Therese;Hangen, Emilie;Saudou, Frederic
通讯作者：
Saudou, Frederic
DOI：
10.1107/s0907444909052925
发表时间：
2010-02
期刊：
Acta crystallographica. Section D, Biological crystallography
影响因子：
--
作者：
Adams PD;Afonine PV;Bunkóczi G;Chen VB;Davis IW;Echols N;Headd JJ;Hung LW;Kapral GJ;Grosse-Kunstleve RW;McCoy AJ;Moriarty NW;Oeffner R;Read RJ;Richardson DC;Richardson JS;Terwilliger TC;Zwart PH
通讯作者：
Zwart PH
影响因子：
3
作者：
Pettersen, EF;Goddard, TD;Ferrin, TE
通讯作者：
Ferrin, TE
DOI：
10.1107/s0907444909042073
发表时间：
2010-01
期刊：
Acta crystallographica. Section D, Biological crystallography
影响因子：
--
作者：
Chen VB;Arendall WB 3rd;Headd JJ;Keedy DA;Immormino RM;Kapral GJ;Murray LW;Richardson JS;Richardson DC
通讯作者：
Richardson DC