Structural characterization of life-extending Caenorhabditis elegans Lipid Binding Protein 8

• Type of Material: Article
• Authors: Matthew C. Tillman, Emory University; Manoj Khadka, Emory University; Jonathon Duffy, Baylor College of Medicine; Meng C. Wang, Baylor College of Medicine; Eric Ortlund, Emory University
• Language: English
• Date: 2019-07-10
• Publisher: Nature Research (part of Springer Nature): Fully open access journals
• Publication Version: Final Published Version
• Copyright Statement: © 2019, The Author(s).
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1038/s41598-019-46230-8
• Title of Journal or Parent Work: Scientific Reports
• ISSN: 2045-2322
• Volume: 9
• Issue: 1
• Start Page: 9966
• End Page: 9966
• Grant/Funding Information: M.C.T. was funded by the T32 GM008602 NIH Pharmacology Training Grant.; Additional support was provided by the Georgia Clinical & Translational Science Alliance of the National Institutes of Health under Award Number UL1TR002378.; M.C.W. was supported by R01AG045183, R01AT009050, DP1DK113644 and the HHMI.; This study was supported in part by the Emory Integrated Lipidomics Core (EILC), which is subsidized by the Emory University School of Medicine and is one of the Emory Integrated Core Facilities.; E.A.O. was supported by R01DK115213 and the W.M. Keck Foundation.; Crystallographic data were collected at Southeast Regional Collaborative Access Team (SER-CAT) 22-ID beamline at the Advanced Photon Source, Argonne National Laboratory, and was supported by the United States Department of Energy, Office of Science, Office of Basic Energy Sciences, under contract W-31–109-Eng-38.
• Keywords: FAMILY; OLEIC-ACID; COMPLEX; MTOR; ALPHA; Science & Technology - Other Topics; ACTIVATION; Science & Technology; METABOLISM; SYSTEM; IDENTIFICATION; FATTY-ACID-BINDING; Multidisciplinary Sciences
• Research Categories: Chemistry, Biochemistry

Abstract

The lysosome plays a crucial role in the regulation of longevity. Lysosomal degradation is tightly coupled with autophagy that is induced by many longevity paradigms and required for lifespan extension. The lysosome also serves as a hub for signal transduction and regulates longevity via affecting nuclear transcription. One lysosome-to-nucleus retrograde signaling pathway is mediated by a lysosome-associated fatty acid binding protein LBP-8 in Caenorhabditis elegans. LBP-8 shuttles lysosomal lipids into the nucleus to activate lipid regulated nuclear receptors NHR-49 and NHR-80 and consequently promote longevity. However, the structural basis of LBP-8 action remains unclear. Here, we determined the first 1.3 Å high-resolution structure of this life-extending protein LBP-8, which allowed us to identify a structurally conserved nuclear localization signal and amino acids involved in lipid binding. Additionally, we described the range of fatty acids LBP-8 is capable of binding and show that it binds to life-extending ligands in worms such as oleic acid and oleoylethanolamide with high affinity.