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.
Highlights
Two alleles of the mammalian Ras protein acyltransferase are associated with X-linked intellectual disabilities
This study addresses the molecular defect manifested by the two missense genetic variants that map within the zDHHC9 gene and are linked to the Marfanoid features as well as the psychological disorders representative of syndromic X-linked intellectual disorders (XLIDs)
Alignment of the Ras protein acyltransferases (PATs) subfamily that consists of yeast Erf2 and mammalian zDHHC9 reveals additional conserved residues that include a (R/K)PXR motif juxtaposed to the catalytic DHHC motif (Fig. 1B)
Summary
Two alleles of the mammalian Ras protein acyltransferase are associated with X-linked intellectual disabilities. A substrate-enzyme (PAT) intermediate is formed via a thioester linkage between palmitate from palmitoyl-CoA and the cysteine of the DHHC motif, a process referred to as autopalmitoylation [15]. This study addresses the molecular defect manifested by the two missense genetic variants that map within the zDHHC9 gene and are linked to the Marfanoid features as well as the psychological disorders representative of syndromic XLIDs. We provide genetic and biochemical evidence that zDHHC9 R148W and zDHHC9 P150S reduce the steady state level of autopalmitoylated zDHHC9 through different mechanisms. The R148W mutation increases the hydrolysis rate of the zDHHC9-palmitate thioester linkage, whereas the P150S mutation decreases the initial burst phase of the autopalmitoylation reaction Both mutations affect the steady state level of the zDHHC9-palmitate intermediate, which in turn is predicted to affect palmitoylation target proteins involved in intellectual development
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