Primate-specific regulation of the human glycosphingolipid gatekeeper UGCG

• 成果类型: Article
• 署名作者: Wu, Canrong; Jin, Sanshan; Xu, Jiuyin; Wang, James Jiqi; Guo, Xiaoqi; Li, Yunhai; Cao, Zhenyu; Jiang, Mengting; Yuan, Qingning; Hu, Wen; Li, Changyao; Xu, Youwei; Wang, Ming-Wei; Jiang, Yi; Xu, H. Eric
• 署名单位: Shanghai Jiao Tong University; Lin Gang Laboratory; ShanghaiTech University; Huazhong University of Science & Technology; Huazhong University of Science & Technology; Nanjing Medical University; Xiamen University; Nanjing University of Chinese Medicine; Chinese Academy of Sciences; Shanghai Institute of Materia Medica, CAS; Chinese Academy of Sciences; University of Chinese Academy of Sciences, CAS
• 刊物名称: NATURE
• ISSN/ISSBN: 0028-0836; 1476-4687
• DOI: 10.1038/s41586-026-10927-4
• 发表日期: 2026-09-10
• 关键词: alpha-synuclein; DISEASE TYPE-1; glucocerebrosidase; ELIGLUSTAT; therapy; RAFTS

摘要

Glycosphingolipids are essential membrane components that organize lipid microdomains and orchestrate cellular signalling, differentiation and neuronal function1, 2, 3-4. In humans, these functions arise from a repertoire of several hundred glycosphingolipid species generated through stepwise glycan elaboration5,6. Entry into this network is controlled by a single committed reaction catalysed by UDP-glucose ceramide glucosyltransferase (UGCG), the gatekeeper that dictates the scale and composition of glycosphingolipid diversity. Despite its biological and therapeutic importance7,8, its mechanism and regulation have remained unknown. Here we report cryogenic electron microscopy structures of full-length human UGCG in eight functional states at 2.9-3.4 & Aring; resolution. UGCG adopts a previously unrecognized triple-pass transmembrane architecture that anchors a GT-A core at the membrane interface and creates a bipartite active site engaging soluble and membrane-embedded substrates. Contrary to canonical GT-A enzymes, UGCG uses a metal-independent catalytic mechanism driven by an arginine network. We identify a primate-specific steric element that tunes lipid affinity and catalytic turnover, modulating glycosphingolipid entry. Structures with clinically used inhibitors reveal how this architecture governs their potency and selectivity. Together, these findings define the structural and evolutionary logic by which one enzyme controls glycosphingolipid diversity and provide a framework for precision modulation of membrane lipid homeostasis in disease.