Palmitoylated acyl protein thioesterase APT2 deforms membranes to extract substrate acyl chains

Abrami, Laurence; Audagnotto, Martina; S, Ho; Marcaida, M.J.; Mesquita, Francisco; Anwar, Muhammad U.; Sandoz, Patrick A.; Fonti, Giulia; Pojer, F.; Peraro, Matteo Dal; Goot, F. Gisou van der

doi:10.1038/s41589-021-00753-2

Cited by 39 publications

(60 citation statements)

References 46 publications

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“…Mechanistically, APT2 can associate with membranes in three different ways: through electrostatic attraction, insertion of a hydrophobic loop and through palmitoylation by either zDHHC3 or 7. Once bound to the membrane, APT2 is predicted to deform the lipid bilayer and trigger extraction of the acyl chain to capture it in its hydrophobic pocket (75). In addition, Kathayat et al developed a fluorescent probe for S-depalmitoylation activity to monitor the endogenous activity levels of APTs and confirmed that APTs activity is dynamically regulated (76).…”

Section: Protein Depalmitoylation and Aptsmentioning

confidence: 99%

Function of Protein S-Palmitoylation in Immunity and Immune-Related Diseases

et al. 2021

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Protein S-palmitoylation is a covalent and reversible lipid modification that specifically targets cysteine residues within many eukaryotic proteins. In mammalian cells, the ubiquitous palmitoyltransferases (PATs) and serine hydrolases, including acyl protein thioesterases (APTs), catalyze the addition and removal of palmitate, respectively. The attachment of palmitoyl groups alters the membrane affinity of the substrate protein changing its subcellular localization, stability, and protein-protein interactions. Forty years of research has led to the understanding of the role of protein palmitoylation in significantly regulating protein function in a variety of biological processes. Recent global profiling of immune cells has identified a large body of S-palmitoylated immunity-associated proteins. Localization of many immune molecules to the cellular membrane is required for the proper activation of innate and adaptive immune signaling. Emerging evidence has unveiled the crucial roles that palmitoylation plays to immune function, especially in partitioning immune signaling proteins to the membrane as well as to lipid rafts. More importantly, aberrant PAT activity and fluctuations in palmitoylation levels are strongly correlated with human immunologic diseases, such as sensory incompetence or over-response to pathogens. Therefore, targeting palmitoylation is a novel therapeutic approach for treating human immunologic diseases. In this review, we discuss the role that palmitoylation plays in both immunity and immunologic diseases as well as the significant potential of targeting palmitoylation in disease treatment.

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Section: Protein Depalmitoylation and Aptsmentioning

confidence: 99%

Function of Protein S-Palmitoylation in Immunity and Immune-Related Diseases

et al. 2021

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“…The consensus is that to mediate depalmitoylation of their substrates the cytoplasmic depalmitoylating enzymes need to come into proximity with the membrane. Indeed, ATP1, APT2, and ABHD17A–C have all been shown to be palmitoylated themselves [ 97–99 ] and an interesting new mechanism of membrane binding was just identified for APT2 [ 100 ]. This study from the van der Goot group showed that APT2 binds membranes in a three-step process where long-range electrostatic interactions attract APT2 to the lipid membrane.…”

Section: A Primer On Palmitoylationmentioning

confidence: 99%

“…This study from the van der Goot group showed that APT2 binds membranes in a three-step process where long-range electrostatic interactions attract APT2 to the lipid membrane. This then allows the β-tongue of APT2 to dip into the membrane, temporarily holding APT2 in place, allowing its subsequent palmitoylation by ZDHHC3 or ZDHHC7, thereby stably binding it to the membrane [ 100 ]. After APT2 identifies a target protein, it extracts palmitate from the membrane into its catalytic hydrophobic pocket for hydrolysis [ 100 ].…”

Section: A Primer On Palmitoylationmentioning

confidence: 99%

“…This then allows the β-tongue of APT2 to dip into the membrane, temporarily holding APT2 in place, allowing its subsequent palmitoylation by ZDHHC3 or ZDHHC7, thereby stably binding it to the membrane [ 100 ]. After APT2 identifies a target protein, it extracts palmitate from the membrane into its catalytic hydrophobic pocket for hydrolysis [ 100 ]. It will be interesting to see if the other depalmitoylating enzymes use similar mechanisms.…”

Section: A Primer On Palmitoylationmentioning

confidence: 99%

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A sticky situation: regulation and function of protein palmitoylation with a spotlight on the axon and axon initial segment

et al. 2021

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In neurons, the axon and axon initial segment (AIS) are critical structures for action potential initiation and propagation. Their formation and function rely on tight compartmentalization, a process where specific proteins are trafficked to and retained at distinct subcellular locations. One mechanism which regulates protein trafficking and association with lipid membranes is the modification of protein cysteine residues with 16-carbon palmitic acid, known as S-acylation or palmitoylation. Palmitoylation, akin to phosphorylation, is reversible, with palmitate cycling being mediated by substrate-specific enzymes. Palmitoylation is well-known to be highly prevalent among neuronal proteins and is well studied in the context of the synapse. Comparatively, how palmitoylation regulates trafficking and clustering of axonal and AIS proteins remains less understood. This review provides an overview of the current understanding of the biochemical regulation of palmitoylation, its involvement in various neurological diseases, and the most up-to-date perspective on axonal palmitoylation. Through a palmitoylation analysis of the AIS proteome, we also report that an overwhelming proportion of AIS proteins are likely palmitoylated. Overall, our review and analysis confirm a central role for palmitoylation in the formation and function of the axon and AIS and provide a resource for further exploration of palmitoylation-dependent protein targeting to and function at the AIS.

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“…[ 3 H]palmitate radiolabeling was performed as previously described 51 . Briefly, transfected HeLa cells were starved for 1 hr in MEM supplemented with 10 mM HEPES, pH 7.4, and subsequently radiolabeled for 3 hr with 70 μ Ci/ml of [9,10-3 H]palmitate (Cat# ART-0129-25; American Radiolabeled Chemicals, Inc.).…”

Section: Metabolic Radiolabeling With [ 3 H]palmitatementioning

confidence: 99%

Local and substrate-specific S-palmitoylation determines subcellular localization of Gαo

Solis

Valnohová

Álvarez

et al. 2020

Preprint

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Peripheral membrane proteins (PMPs) associate with cellular membranes through post-translational modifications like S-palmitoylation. The Golgi apparatus is generally viewed as the transitory station where palmitoyl acyltransferases (PATs) modify PMPs, which are then transported to their ultimate destinations such as plasma membrane (PM); little substrate specificity among the many PATs has been determined. Here we describe inherent partitioning of Gαo – α-subunit of heterotrimeric Go-proteins – to PM and Golgi, independent from Golgi-to-PM transport. A minimal code within the Gαo N-terminus governs the compartmentalization and re-coding produces G-protein versions with shifted localization. We established the SpONM (S-palmitoylation at the outer nuclear membrane) assay to probe substrate specificity of PATs in intact cells. With this assay, we showed that PATs localizing to different membrane compartments display remarkable substrate selectivity, which is the basis for specific PMP compartmentalization. Our findings uncover the fundamental mechanism governing protein localization and establish the basis for innovative drug discovery.

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Palmitoylated acyl protein thioesterase APT2 deforms membranes to extract substrate acyl chains

Cited by 39 publications

References 46 publications

Function of Protein S-Palmitoylation in Immunity and Immune-Related Diseases

Function of Protein S-Palmitoylation in Immunity and Immune-Related Diseases

A sticky situation: regulation and function of protein palmitoylation with a spotlight on the axon and axon initial segment

Local and substrate-specific S-palmitoylation determines subcellular localization of Gαo

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