Crystal structure of a bacterial homolog to human lysosomal transporter, spinster

Fu Zhou; Deqiang Yao; Bing Rao; Li Zhang; Wang Nie; Yan Zou; Jie Zhao; Yu Cao

doi:10.1016/j.scib.2019.08.010

Crystal structure of a bacterial homolog to human lysosomal transporter, spinster

Sci Bull (Beijing). 2019 Sep 30;64(18):1310-1317. doi: 10.1016/j.scib.2019.08.010. Epub 2019 Aug 12.

Authors

Fu Zhou¹, Deqiang Yao², Bing Rao¹, Li Zhang¹, Wang Nie³, Yan Zou³, Jie Zhao⁴, Yu Cao⁵

Affiliations

¹ CAS Center for Excellence on Molecular Cell Science, Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 201210, China.
² Institute of Precision Medicine, The Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200125, China.
³ School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China.
⁴ Department of Orthopaedics, Shanghai Key Laboratory of Orthopaedic Implant, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China. Electronic address: 13301815365@189.cn.
⁵ Institute of Precision Medicine, The Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200125, China; Department of Orthopaedics, Shanghai Key Laboratory of Orthopaedic Implant, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China. Electronic address: yu.cao@shsmu.edu.cn.

PMID: 36659660
DOI: 10.1016/j.scib.2019.08.010

Abstract

Lysosomes break down various biomolecules and spinster is one of the major efflux carriers removing degradation products from lysosomal lumen to keep it in healthy size and proper function. Although it is well established that a dysfunctional spinster will cause enlarged lysosomes and in turn lead to developmental defects and abnormal behavior in animals, little was known about the transportation mechanism and substrate specificity of spinster. Here, we report a crystal structure of spinster homolog from Hyphomonas neptunium, HnSPNS, in its inward-facing conformation with and without substrate bound. HnSPNS is crystallized in a monomer and a substrate-binding cavity was formed in the center of its transmembrane helices. A blob of electron density corresponding to its substrate was found in the cavity near a conserved residue, R42, which is locked in position by the interactions with conserved residues E129 and R122. Our results suggest that human spinster serves as a transporter translocating negatively-charged lipophilic small molecules and E129 might serve as a switch to control the conformational change via its protonation-deprotonation cycle.

Keywords: Major facilitator superfamily; Membrane protein; Spinster; Transporter.