title: Mutations in the X-linked intellectual disability gene, zDHHC9, alter autopalmitoylation activity by distinct mechanisms.
abstract: Early onset intellectual disabilities result in significant societal and economic costs and affect 1-3% of the population. The underlying genetic determinants are beginning to emerge and are interpreted in the context of years of work characterizing postsynaptic receptor and signaling functions of learning and memory. DNA sequence analysis of intellectual disability patients has revealed greater than 80 loci on the X-chromosome that are potentially linked to disease. One of the loci is zDHHC9, a gene encoding a Ras protein acyltransferase. Protein palmitoylation is a reversible modification that controls the subcellular localization and distribution of membrane receptors, scaffolds, and signaling proteins required for neuronal plasticity. Palmitoylation occurs in two steps. In the first step, autopalmitoylation, an enzyme-palmitoyl intermediate is formed. During the second step, the palmitoyl moiety is transferred to a protein substrate, or if no substrate is available, hydrolysis of the thioester linkage produces the enzyme and free palmitate. In this study, we demonstrate that two naturally occurring variants of zDHHC9, encoding R148W and P150S, affect the autopalmitoylation step of the reaction by lowering the steady state amount of the palmitoyl-zDHHC9 intermediate.
authors.affiliation: From the Department of Molecular Medicine, University of South Florida, Tampa, Florida 33612 and.
authors.forename: David A
authors.initials: DA
authors.lastname: Mitchell
authors.affiliation: From the Department of Molecular Medicine, University of South Florida, Tampa, Florida 33612 and.
authors.forename: Laura D
authors.initials: LD
authors.lastname: Hamel
authors.affiliation: From the Department of Molecular Medicine, University of South Florida, Tampa, Florida 33612 and.
authors.forename: Krishna D
authors.initials: KD
authors.lastname: Reddy
authors.affiliation: the Department of Chemical Biology, National Pingtung University, Pingtung 900-03, Taiwan.
authors.forename: Lynn
authors.initials: L
authors.lastname: Farh
authors.affiliation: From the Department of Molecular Medicine, University of South Florida, Tampa, Florida 33612 and.
authors.forename: Logan M
authors.initials: LM
authors.lastname: Rettew
authors.affiliation: From the Department of Molecular Medicine, University of South Florida, Tampa, Florida 33612 and.
authors.forename: Phillip R
authors.initials: PR
authors.lastname: Sanchez
authors.affiliation: From the Department of Molecular Medicine, University of South Florida, Tampa, Florida 33612 and rdeschen@health.usf.edu.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Deschenes
mesh_terms: D000217:Acyltransferases / Q000235:genetics* / Q000378:metabolism*; D000595:Amino Acid Sequence; D041321:Chromosomes, Human, X / Q000235:genetics* / Q000378:metabolism; D005260:Female; D006801:Humans; D008607:Intellectual Disability / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism; D054878:Lipoylation; D008297:Male; D008969:Molecular Sequence Data; D020125:Mutation, Missense
chemical_list: D000217:Acyltransferases; C504825:ZDHHC9 protein, human
keywords: Enzyme Mechanism; Post-translational Modification (PTM); Protein Acylation; Protein Palmitoylation; Ras Protein; X-linked Intellectual Disability; zDHHC Proteins