Mechanisms and functions of protein S-acylation

S. Mesquita, Francisco; Abrami, Laurence; Linder, Maurine E.; Bamji, Shernaz X.; Dickinson, Bryan C.; van der Goot, F. Gisou

doi:10.1038/s41580-024-00700-8

Cited by 25 publications

(12 citation statements)

References 263 publications

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“…S-acylation of CLMB is dynamic and mediates membrane association. S-acylation, the only protein lipidation that is reversible, turns over rapidly for some proteins, while others are stably modified 12 . To examine the dynamics of CLMB-FLAG S-acylation we carried out a pair of pulsechase analyses with two metabolic labels (Figure 1D and 1E).…”

Section: Resultsmentioning

confidence: 99%

“…C16orf74 contains an N-terminal glycine (G2), a common site for N-myristoylation, the co-translational addition of a 14-carbon lipid which often contributes to membrane association in combination with other lipid modifications 16 . These include S-acylation, the reversible addition of a fatty acid, usually a 16-carbon palmitate, to the sidechain of cysteine residues 12 . CLMB has two cysteines near in its N-terminus, Cys7 and Cys14, one of which, Cys7, is predicted to be palmitoylated 17 .…”

Section: Resultsmentioning

confidence: 99%

“…In this work we show that CLMB associates with membranes via two lipid modifications, N-myristoylation and S-acylation. S-acylation, the only protein lipidation that is reversible, regulates many aspects of signaling at membranes 12 . In addition to CLMB, S-acylation modulates CN activity through at least two additional mechanisms: S-acylation regulates subcellular localization of the AKAP5 scaffold in neurons to control long-term synaptic potentiation 13 .…”

Section: Introductionmentioning

confidence: 99%

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A novel motif in calcimembrin/C16orf74 dictates multimeric dephosphorylation by calcineurin

Bradburn,

Reis,

Qayyum

et al. 2024

Preprint

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Calcineurin (CN), the only Ca2+-calmodulin activated protein phosphatase, dephosphorylates substrates within membrane-associated Ca2+ microdomains. CN binds to substrates and regulators via short linear motifs (SLIMs), PxIxIT and LxVP. PxIxIT binding to CN is Ca2+ independent and affects its distribution, while LxVP associates only with the active enzyme and promotes catalysis. 31 human proteins contain one or more composite LxVPxIxIT motifs, whose functional properties have not been examined. Here we report studies of calcimembrin/C16orf74 (CLMB), a largely uncharacterized protein containing a composite motif that binds and directs CN to membranes. We demonstrate that CLMB associates with membranes via N-myristoylation and dynamic S-acylation and is dephosphorylated by CN on Thr44. The LxVP and PxIxIT portions of the CLMB composite sequence, together with Thr44 phosphorylation, confer high affinity PxIxIT-mediated binding to CN (KD~8.9 nM) via an extended, 33LxVPxIxITxx(p)T44 sequence. This binding promotes CLMB-based targeting of CN to membranes, but also protects Thr44 from dephosphorylation. Thus, we propose that CN dephosphorylates CLMB in multimeric complexes, where one CLMB molecule recruits CN to membranes via PxIxIT binding, allowing others to engage through their LxVP motif for dephosphorylation. This unique mechanism makes dephosphorylation sensitive to CLMB:CN ratios and is supported by in vivo and in vitro analyses. CLMB overexpression is associated with poor prognoses for several cancers, suggesting that it promotes oncogenesis by shaping CN signaling.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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A novel motif in calcimembrin/C16orf74 dictates multimeric dephosphorylation by calcineurin

Bradburn,

Reis,

Qayyum

et al. 2024

Preprint

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“…It should be noted that protein palmitoylation, a type of protein lipidation involving the post-translational addition of a lipid to a protein, specifically entails the thioesterification of a sixteen-carbon saturated fatty acid (palmitate) to an internal cysteine residue. This process can influence protein localization, accumulation, secretion, stability, and function by altering membrane affinity ( 37 ). The C-terminal peptide of Bradyrhizobium bGSDM terminates below the equivalent of the β2 strand and is supported by hydrogen bonds from R27 to the L256 backbone and N29 to E258 ( 16 ).…”

Section: Gsdm Homolog In Bacteriamentioning

confidence: 99%

Evolutionary insights and functional diversity of gasdermin family proteins and homologs in microorganisms

Wang,

Ma,

Xia

et al. 2024

Front. Immunol.

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The gasdermin protein family and its homologs in microorganisms have gained significant attention due to their roles in programmed cell death, immune defense, and microbial infection. This review summarizes the current research status of gasdermin proteins, their structural features, and functional roles in fungi, bacteria, and viruses. The review presents evolutionary parallels between mammalian and microbial defense systems, highlighting the conserved role of gasdermin proteins in regulating cell death processes and immunity. Additionally, the structural and functional characteristics of gasdermin homologs in microorganisms are summarized, shedding light on their potential as targets for therapeutic interventions. Future research directions in this field are also discussed to provide a roadmap for further investigation.

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“…S-acylation, which involves the post-translational addition of a long chain fatty acid to cysteine residues, is the only reversible lipid modification. Dynamic S-acylation has been shown to influence protein localization, stability and activity and is important for cellular processes such as signaling and growth (reviewed in Chen et al, 2021 andS Mesquita et al, 2024). For example, NRas undergoes a cycle of acyl chain addition and removal that regulates its localization at the plasma membrane and is essential for oncogenic signaling (Remsberg et al, 2021;Xu et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

An acylated N-terminus and a conserved loop regulate the activity of the ABHD17 de-acylase

Holme,

Sapia,

Davey

et al. 2024

Preprint

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The dynamic addition and removal of long chain fatty acids modulates protein function and localization. The alpha/beta hydrolase domain-containing (ABHD) 17 enzymes remove acyl chains from membrane localized proteins such as the oncoprotein NRas, but how the ABHD17 proteins are regulated is unknown. Here, we used cell-based studies and molecular dynamics simulations to show that ABHD17 activity is controlled by two mobile elements - an S-acylated N-terminal helix and a loop - that flank the substrate-binding pocket. S-acylation at multiple sites buries the helix in the membrane, which allows hydrophobic residues in the loop to interact with the bilayer. This stabilizes the conformation of both helix and loop, alters the conformation of the binding pocket and optimally positions the enzyme for substrate engagement. S-acylation may be a general feature of acyl-protein thioesterases. By providing a mechanistic understanding of how the lipid modification of a lipid-removing enzyme promotes its enzymatic activity, this work contributes to our understanding of cellular S-acylation cycles.

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Mechanisms and functions of protein S-acylation

Cited by 25 publications

References 263 publications

A novel motif in calcimembrin/C16orf74 dictates multimeric dephosphorylation by calcineurin

A novel motif in calcimembrin/C16orf74 dictates multimeric dephosphorylation by calcineurin

Evolutionary insights and functional diversity of gasdermin family proteins and homologs in microorganisms

An acylated N-terminus and a conserved loop regulate the activity of the ABHD17 de-acylase

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