title: A Global Map of Lipid-Binding Proteins and Their Ligandability in Cells.
abstract: Lipids play central roles in physiology and disease, where their structural, metabolic, and signaling functions often arise from interactions with proteins. Here, we describe a set of lipid-based chemical proteomic probes and their global interaction map in mammalian cells. These interactions involve hundreds of proteins from diverse functional classes and frequently occur at sites of drug action. We determine the target profiles for several drugs across the lipid-interaction proteome, revealing that its ligandable content extends far beyond traditionally defined categories of druggable proteins. In further support of this finding, we describe a selective ligand for the lipid-binding protein nucleobindin-1 (NUCB1) and show that this compound perturbs the hydrolytic and oxidative metabolism of endocannabinoids in cells. The described chemical proteomic platform thus provides an integrated path to both discover and pharmacologically characterize a wide range of proteins that participate in lipid pathways in cells.
authors.affiliation: The Skaggs Institute for Chemical Biology and Department of Chemical Physiology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA. Electronic address: mniphak@gmail.com.
authors.forename: Micah J
authors.initials: MJ
authors.lastname: Niphakis
authors.affiliation: The Skaggs Institute for Chemical Biology and Department of Chemical Physiology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Kenneth M
authors.initials: KM
authors.lastname: Lum
authors.affiliation: The Skaggs Institute for Chemical Biology and Department of Chemical Physiology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Armand B
authors.initials: AB
authors.lastname: Cognetta
authors.affiliation: The Skaggs Institute for Chemical Biology and Department of Chemical Physiology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Bruno E
authors.initials: BE
authors.lastname: Correia
authors.affiliation: The Skaggs Institute for Chemical Biology and Department of Chemical Physiology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Taka-Aki
authors.initials: TA
authors.lastname: Ichu
authors.affiliation: The Skaggs Institute for Chemical Biology and Department of Chemical Physiology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Jose
authors.initials: J
authors.lastname: Olucha
authors.affiliation: The Skaggs Institute for Chemical Biology and Department of Chemical Physiology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Brown
authors.affiliation: The Skaggs Institute for Chemical Biology and Department of Chemical Physiology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Soumajit
authors.initials: S
authors.lastname: Kundu
authors.affiliation: The Skaggs Institute for Chemical Biology and Department of Chemical Physiology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Fabiana
authors.initials: F
authors.lastname: Piscitelli
authors.affiliation: The Skaggs Institute for Chemical Biology and Department of Chemical Physiology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Hugh
authors.initials: H
authors.lastname: Rosen
authors.affiliation: The Skaggs Institute for Chemical Biology and Department of Chemical Physiology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA. Electronic address: cravatt@scripps.edu.
authors.forename: Benjamin F
authors.initials: BF
authors.lastname: Cravatt
mesh_terms: D000818:Animals; D002135:Calcium-Binding Proteins / Q000032:analysis; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000032:analysis; D004353:Drug Evaluation, Preclinical; D015777:Eicosanoids / Q000378:metabolism; D063388:Endocannabinoids / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D050356:Lipid Metabolism / Q000187:drug effects; D051379:Mice; D009419:Nerve Tissue Proteins / Q000032:analysis; D000080866:Nucleobindins; D011506:Proteins / Q000032:analysis* / Q000378:metabolism*; D020543:Proteome / Q000032:analysis / Q000378:metabolism; D054852:Small Molecule Libraries / Q000494:pharmacology
chemical_list: D002135:Calcium-Binding Proteins; D004268:DNA-Binding Proteins; D015777:Eicosanoids; D063388:Endocannabinoids; C000630649:NUCB1 protein, human; D009419:Nerve Tissue Proteins; D000080866:Nucleobindins; D011506:Proteins; D020543:Proteome; D054852:Small Molecule Libraries