Mutations in the X-linked Intellectual Disability Gene, zDHHC9, Alter Autopalmitoylation Activity by Distinct Mechanisms

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 l...

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Bibliographic Details
Published in:The Journal of biological chemistry 2014-06, Vol.289 (26), p.18582-18592
Main Authors: Mitchell, David A., Hamel, Laura D., Reddy, Krishna D., Farh, Lynn, Rettew, Logan M., Sanchez, Phillip R., Deschenes, Robert J.
Format: Article
Language:English
Subjects:
Acyltransferases - genetics
Acyltransferases - metabolism
Amino Acid Sequence
Chromosomes, Human, X - genetics
Chromosomes, Human, X - metabolism
Enzyme Mechanism
Female
Humans
Intellectual Disability - enzymology
Intellectual Disability - genetics
Intellectual Disability - metabolism
Lipoylation
Male
Membrane Biology
Molecular Sequence Data
Mutation, Missense
Post-translational Modification (PTM)
Protein Acylation
Protein Palmitoylation
Ras Protein
X-linked Intellectual Disability
zDHHC Proteins
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Summary: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. Background: Two alleles of the mammalian Ras protein acyltransferase are associated with X-linked intellectual disabilities. Results: Mutations of zDHHC9 isolated from XLID patients result in defects to steady state autopalmitoylation levels. Conclusion: Although the zDHHC9 mutations produce similar phenotypes, they are guided by distinct mechanisms. Significance: Elucidation of the catalytic mechanism of PATs is a critical step in designing pharmacological interventions.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M114.567420