人源CLC-7/Ostm1复合物结构揭示一种新构象  

Structure of the human CLC-7/Ostm1 complex reveals a novel state

作　　者：张峙轩 陈龙 贺金 佘继 Zhixuan Zhang;Long Chen;Jin He;Ji She(School of Life Sciences,Division of Life Sciences and Medicine,University of Science and Technology of China,Hefei 230027,China)

机构地区：[1]中国科学技术大学生命科学与医学部生命科学学院,安徽合肥230027

出　　处：《中国科学技术大学学报》2023年第3期54-59,I0003,共7页JUSTC

基　　金：This work was supported by the Ministry of Science and Technology of China(2021YFF0600801);the National Natural Science Foundation of China(32071201);the Fundamental Research Funds for the Central Universities(WK2070000183).

摘　　要：CLC-7是位于溶酶体膜上的Cl^(-)/H^(+)交换转运蛋白。CLC-7及其β亚基Ostm1的缺陷均会导致骨硬化症和神经退行性疾病。本文解析了一个具有3.6Å分辨率的人源CLC-7/Ostm1复合物的冷冻电镜结构。该结构揭示了CLC-7/Ostm1异源四聚体的一种新构象,其中CLC-7的胞质结构域可能由于高度柔性而缺失。柔性的细胞质结构域无法限制CLC-7的跨膜结构域,从而允许两个亚基相对远离,使得CLC-7跨膜结构域的二聚界面与已知具有稳定胞质结构域的结构相比减小了约一半。这种二聚界面的变化影响了多个骨硬化症相关残基的相互作用。CLC-7 functions as a Cl^(−)/H^(+) exchanger in lysosomes.Defects in CLC-7 and itsβ-subunit,Ostm1,result in os-teopetrosis and neurodegeneration.Here,we present the cryogenic electron microscopy(cryo-EM)structure of the human CLC-7/Ostm1 complex(HsCLC-7/Ostm1)at a resolution of 3.6Å.Our structure reveals a new state of the CLC-7/Ostm1 heterotetramer,in which the cytoplasmic domain of CLC-7 is absent,likely due to high flexibility.The disordered cyto-plasmic domain is probably not able to restrain CLC-7 subunits and thus allow their relative movements.The movements result in an approximately half smaller interface between the CLC-7 transmembrane domains than that in a previously re-ported CLC-7/Ostm1 structure with a well-folded cytoplasmic domain.Key interactions involving multiple osteopetrosis-related residues are affected by the interface change.

关 键 词：CLC-7 Ostm1 骨硬化症 氯离子转运蛋白 单颗粒冷冻电镜 

分 类 号：Q71[生物学—分子生物学]