Structural advances in sterol-sensing domain-containing proteins

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

doi:10.1016/j.tibs.2021.12.005

Structural advances in sterol-sensing domain-containing proteins

Trends Biochem Sci. 2022 Apr;47(4):289-300. doi: 10.1016/j.tibs.2021.12.005. Epub 2022 Jan 7.

Authors

Xuelan Wu¹, Renhong Yan², Pingping Cao³, Hongwu Qian⁴, Nieng Yan⁵

Affiliations

¹ Department of Chemistry, Princeton University, Princeton, NJ 08544, USA.
² 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.
³ Department of Molecular Biology, Princeton University, Princeton, NJ 08544, USA.
⁴ 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: hongwuqian@ustc.edu.cn.
⁵ Department of Molecular Biology, Princeton University, Princeton, NJ 08544, USA. Electronic address: nyan@princeton.edu.

PMID: 35012873
DOI: 10.1016/j.tibs.2021.12.005

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.

Keywords: Insig; Niemann-Pick disease type C1 (NPC1); Patched; Scap; cholesterol metabolism; cryo-EM.

Publication types

Review

MeSH terms

Carrier Proteins / metabolism
Intracellular Signaling Peptides and Proteins* / metabolism
Membrane Proteins / metabolism
Niemann-Pick C1 Protein*
Sterols / metabolism

Substances

Carrier Proteins
Intracellular Signaling Peptides and Proteins
Membrane Proteins
Niemann-Pick C1 Protein
Sterols