Dynamic protein acylation and the regulation of localization and function of signal-transducing proteins

Jackson, Caroline S.; Zlatkine, Philippe; Bano, Carmen; Kabouridis, Panagiotis S.; Méhul, Bruno; Parenti, Marco; Milligan, Graeme; Ley, Steven C.; Magee, Anthony I.

doi:10.1042/bst0230568

Cited by 23 publications

(12 citation statements)

References 7 publications

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“…The N terminus also contains three potentially palmitoylatable cysteines. Protein palmitoylation, the thioester linkage of saturated palmitic acid to cysteine, is a reversible process that is dynamically regulated by specific cellular stimuli (30, 31). Palmitoylation serves both to tether proteins to membranes and to direct their localization to membrane microdomains (32, 33).…”

Section: Introductionmentioning

confidence: 99%

Palmitoylation Targets AKAP79 Protein to Lipid Rafts and Promotes Its Regulation of Calcium-sensitive Adenylyl Cyclase Type 8

Delint-Ramírez¹,

Willoughby

Hammond

et al. 2011

Journal of Biological Chemistry

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PKA anchoring proteins (AKAPs) optimize the efficiency of cAMP signaling by clustering interacting partners. Recently, AKAP79 has been reported to directly bind to adenylyl cyclase type 8 (AC8) and to regulate its responsiveness to store-operated Ca2+ entry (SOCE). Although AKAP79 is well targeted to the plasma membrane via phospholipid associations with three N-terminal polybasic regions, recent studies suggest that AKAP79 also has the potential to be palmitoylated, which may specifically allow it to target the lipid rafts where AC8 resides and is regulated by SOCE. In this study, we have addressed the role of palmitoylation of AKAP79 using a combination of pharmacological, mutagenesis, and cell biological approaches. We reveal that AKAP79 is palmitoylated via two cysteines in its N-terminal region. This palmitoylation plays a key role in targeting the AKAP to lipid rafts in HEK-293 cells. Mutation of the two critical cysteines results in exclusion of AKAP79 from lipid rafts and alterations in its membrane diffusion behavior. This is accompanied by a loss of the ability of AKAP79 to regulate SOCE-dependent AC8 activity in intact cells and decreased PKA-dependent phosphorylation of raft proteins, including AC8. We conclude that palmitoylation plays a key role in the targeting and action of AKAP79. This novel property of AKAP79 adds an unexpected regulatory and targeting option for AKAPs, which may be exploited in the cellular context.

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Section: Introductionmentioning

confidence: 99%

Palmitoylation Targets AKAP79 Protein to Lipid Rafts and Promotes Its Regulation of Calcium-sensitive Adenylyl Cyclase Type 8

Delint-Ramírez¹,

Willoughby

Hammond

et al. 2011

Journal of Biological Chemistry

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“…These results suggest a raft localization for eNOS, independently from the presence of cav-1. Recruitment to rafts is indeed a common feature of fatty acylated proteins like eNOS [72]. Our morphological evidence is fully consistent with a localization of eNOS in cav-1-free rafts, because: (i) its distribution was partially overlapping with that of the raft marker ganglioside G M1 , revealed by fluorescent cholera toxin; (ii) it is known that the leading edge of migrating cells, where eNOS is concentrated, is enriched in PI(4,5)P 2 -containing rafts which are thought to regulate protrusive motility at the cell surface [73].…”

Section: Discussionmentioning

confidence: 99%

Endothelial nitric oxide synthase is segregated from caveolin-1 and localizes to the leading edge of migrating cells

Bulotta¹,

Cerullo²,

Barsacchi³

et al. 2006

Experimental Cell Research

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“…The Src-family of kinases have a conserved structure characterized by distinct functional domains (reviewed in, 53,54 ). It includes an amino terminal (N-terminal) motif containing signals for attachment of lipid moieties, [55][56][57] which in the case of Lck are a myristic acid added cotranslationally to glycine at position 2, and palmytic acid attached to juxtapositioned cysteine residues 3 and 5. [58][59][60][61][62][63][64][65] This dual acylation is sufficient for membrane localization of the protein.…”

Section: Regulation Of Lckmentioning

confidence: 99%

Regulation of T‐cell receptor signalling by membrane microdomains

et al. 2004

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SUMMARYThere is now considerable evidence suggesting that the plasma membrane of mammalian cells is compartmentalized by functional lipid raft microdomains. These structures are assemblies of specialized lipids and proteins and have been implicated in diverse biological functions. Analysis of their protein content using proteomics and other methods revealed enrichment of signalling proteins, suggesting a role for these domains in intracellular signalling. In T lymphocytes, structure/function experiments and complementary pharmacological studies have shown that raft microdomains control the localization and function of proteins which are components of signalling pathways regulated by the T-cell antigen receptor (TCR). Based on these studies, a model for TCR phosphorylation in lipid rafts is presented. However, despite substantial progress in the field, critical questions remain. For example, it is unclear if membrane rafts represent a homogeneous population and if their structure is modified upon TCR stimulation. In the future, proteomics and the parallel development of complementary analytical methods will undoubtedly contribute in further delineating the role of lipid rafts in signal transduction mechanisms.

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Dynamic protein acylation and the regulation of localization and function of signal-transducing proteins

Cited by 23 publications

References 7 publications

Palmitoylation Targets AKAP79 Protein to Lipid Rafts and Promotes Its Regulation of Calcium-sensitive Adenylyl Cyclase Type 8

Palmitoylation Targets AKAP79 Protein to Lipid Rafts and Promotes Its Regulation of Calcium-sensitive Adenylyl Cyclase Type 8

Endothelial nitric oxide synthase is segregated from caveolin-1 and localizes to the leading edge of migrating cells

Regulation of T‐cell receptor signalling by membrane microdomains

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