Structural advances in sterol-sensing domain-containing proteins.

Xuelan Wu, Renhong Yan, Pingping Cao, Hongwu Qian, Nieng Yan

Journal: Trends in biochemical sciences 2022;47(4):289-300

PMID: 35012873

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Abstract

The sterol-sensing domain (SSD) is present in several membrane proteins that function in cholesterol metabolism, transport, and signaling. Recent progress in structural studies of SSD-containing proteins, such as sterol regulatory element-binding protein (SREBP)-cleavage activating protein (Scap), Patched, Niemann-Pick disease type C1 (NPC1), and related proteins, reveals a conserved core that is essential for their sterol-dependent functions. This domain, by its name, 'senses' the presence of sterol substrates through interactions and may modulate protein behaviors with changing sterol levels. We summarize recent advances in structural and mechanistic investigations of these proteins and propose to divide them to two classes: M for 'moderator' proteins that regulate sterol metabolism in response to membrane sterol levels, and T for 'transporter' proteins that harbor inner tunnels for cargo trafficking across cellular membranes.

Address: Department of Chemistry, Princeton University, Princeton, NJ 08544, USA.; Westlake Laboratory of Life Sciences and Biomedicine, Key Laboratory of Structural Biology of Zhejiang Province, School of Life Sciences, Westlake University, 18 Shilongshan Road, Hangzhou 310024, Zhejiang Province, China; Institute of Biology, Westlake Institute for Advanced Study, 18 Shilongshan Road, Hangzhou 310024, Zhejiang Province, China.; Department of Molecular Biology, Princeton University, Princeton, NJ 08544, USA.; Ministry of Education (MOE) Key Laboratory of Membraneless Organelles and Cellular Dynamics, Hefei National Laboratory for Physical Sciences at the Microscale, and Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China. Electronic address: [email protected].; Department of Molecular Biology, Princeton University, Princeton, NJ 08544, USA. Electronic address: [email protected].

DOI: 10.1016/j.tibs.2021.12.005

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MeSH Terms: Carrier Proteins, Intracellular Signaling Peptides and Proteins, Membrane Proteins, Niemann-Pick C1 Protein, Sterols