Structural basis for proton coupled cystine transport by cystinosin.
Structural basis for proton coupled cystine transport by cystinosin.
复制标题
DOI：
10.1038/s41467-022-32589-2
复制
发表时间：
2022-08-17
影响因子：
16.6
通讯作者：
中科院分区：
文献类型：
--
作者：
氨基酸转运蛋白在控制营养物质跨溶酶体膜流动和调节细胞代谢中起关键作用。编码转运蛋白胱氨酸蛋白的基因突变导致胱氨酸沉积症，这是一种常染色体隐性代谢疾病，其特征是胱氨酸晶体在溶酶体中积累。胱氨酸蛋白酶是溶质载体（SLC）转运蛋白的PQ环家族的成员，并使用质子梯度驱动胱氨酸输出到细胞质中。然而，半胱氨酸蛋白酶功能的分子基础仍然难以捉摸，阻碍了开发胱氨酸病的新治疗方法和了解PQ环家族中离子驱动转运机制的努力。为了解决这些问题，我们提出了晶体结构的半胱氨酸蛋白酶从拟南芥在载脂蛋白和胱氨酸结合状态。使用基于体外和体内测定的组合，我们建立了胱氨酸识别和质子偶联转运的机制。人类半胱氨酸蛋白酶的突变定位和功能表征进一步为理解致病突变的分子影响提供了一个框架。CTNS（溶酶体胱氨酸-质子同向转运体）的突变导致胱氨酸病。本文报道了拟南芥CTNS与胱氨酸复合物的晶体结构，并建立了配体识别模式和质子偶联胱氨酸从溶酶体输出的机制。
Amino acid transporters play a key role controlling the flow of nutrients across the lysosomal membrane and regulating metabolism in the cell. Mutations in the gene encoding the transporter cystinosin result in cystinosis, an autosomal recessive metabolic disorder characterised by the accumulation of cystine crystals in the lysosome. Cystinosin is a member of the PQ-loop family of solute carrier (SLC) transporters and uses the proton gradient to drive cystine export into the cytoplasm. However, the molecular basis for cystinosin function remains elusive, hampering efforts to develop novel treatments for cystinosis and understand the mechanisms of ion driven transport in the PQ-loop family. To address these questions, we present the crystal structures of cystinosin from Arabidopsis thaliana in both apo and cystine bound states. Using a combination of in vitro and in vivo based assays, we establish a mechanism for cystine recognition and proton coupled transport. Mutational mapping and functional characterisation of human cystinosin further provide a framework for understanding the molecular impact of disease-causing mutations. Mutations in CTNS, the lysosomal cystine-proton symporter, cause cystinosis. Here authors report crystal structures of CTNS from Arabidopsis thaliana in complex with cystine, and establish the mode of ligand recognition and mechanism for proton-coupled cystine export from the lysosome.
登录
查看更多内容
影响因子：
64.8
作者：
Jumper J;Evans R;Pritzel A;Green T;Figurnov M;Ronneberger O;Tunyasuvunakool K;Bates R;Žídek A;Potapenko A;Bridgland A;Meyer C;Kohl SAA;Ballard AJ;Cowie A;Romera-Paredes B;Nikolov S;Jain R;Adler J;Back T;Petersen S;Reiman D;Clancy E;Zielinski M;Steinegger M;Pacholska M;Berghammer T;Bodenstein S;Silver D;Vinyals O;Senior AW;Kavukcuoglu K;Kohli P;Hassabis D
通讯作者：
Hassabis D
影响因子：
64.5
作者：
Latorraca NR;Fastman NM;Venkatakrishnan AJ;Frommer WB;Dror RO;Feng L
通讯作者：
Feng L
影响因子：
14.8
作者：
Drew, David;Newstead, Simon;Iwata, So
通讯作者：
Iwata, So
DOI：
10.1007/978-1-0716-0373-4_12
发表时间：
2020-01-01
期刊：
EXPRESSION, PURIFICATION, AND STRUCTURAL BIOLOGY OF MEMBRANE PROTEINS
影响因子：
--
作者：
Brunner, Janine Denise;Schenck, Stephan
通讯作者：
Schenck, Stephan
DOI：
10.1107/s0907444904016427
发表时间：
2004-12-01
影响因子：
2.2
作者：
Blanc, E;Roversi, P;Bricogne, G
通讯作者：
Bricogne, G