Site-specific S-Acylation of Influenza Virus Hemagglutinin

Brett, Katharina; Kordyukova, Larisa V.; Serebryakova, Marina V.; Mintaev, Ramil R.; Alexeevski, Andrei V.; Veit, Michael

doi:10.1074/jbc.m114.586180

Cited by 46 publications

(28 citation statements)

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“…For proteins with multiple palmitoylated cysteines, the heterogeneous fatty acylation pattern is different for each cysteine. For example, the hemagglutinin protein (HA) of influenza virus is S-acylated at three cysteines: two contain only palmitate whereas a cysteine residue near the end of the TMD is modified by stearate[77]. The location of the cysteine relative to the TMD was shown to be critical for stearate attachment.…”

Section: Protein Palmitoylationmentioning

confidence: 99%

Fatty acylation of proteins: The long and the short of it

Resh

2016

Progress in Lipid Research

238

235

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Long, short and medium chain fatty acids are covalently attached to hundreds of proteins. Each fatty acid confers distinct biochemical properties, enabling fatty acylation to regulate intracellular trafficking, subcellular localization, protein-protein and protein-lipid interactions. Myristate and palmitate represent the most common fatty acid modifying groups. New insights into how fatty acylation reactions are catalyzed, and how fatty acylation regulates protein structure and function continue to emerge. Myristate is typically linked to an N-terminal glycine, but recent studies reveal that lysines can also be myristoylated. Enzymes that remove N-terminal myristoyl-glycine or myristate from lysines have now been identified. DHHC proteins catalyze S-palmitoylation, but the mechanisms that regulate substrate recognition by individual DHHC family members remain to be determined. New studies continue to reveal thioesterases that remove palmitate from S-acylated proteins. Another area of rapid expansion is fatty acylation of the secreted proteins Hedgehog, Wnt and Ghrelin, by Hhat, Porcupine and GOAT, respectively. Understanding how these membrane bound O-acyl transferases recognize their protein and fatty acyl CoA substrates is an active area of investigation, and is punctuated by the finding that these enzymes are potential drug targets in human diseases.

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Section: Protein Palmitoylationmentioning

confidence: 99%

Fatty acylation of proteins: The long and the short of it

Resh

2016

Progress in Lipid Research

238

235

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“…Another viral S-acylated protein is the hemagglutinin of Influenza virus. S-acylation of its all three cysteine residues by the host cell S-acylation machinery is essential for the replication and infection of the virus (Zurcher et al, 1994; Wagner et al, 2005; Brett et al, 2014). …”

Section: S-acylationmentioning

confidence: 99%

Progress toward Understanding Protein S-acylation: Prospective in Plants

2017

Front. Plant Sci.

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S-acylation, also known as S-palmitoylation or palmitoylation, is a reversible post-translational lipid modification in which long chain fatty acid, usually the 16-carbon palmitate, covalently attaches to a cysteine residue(s) throughout the protein via a thioester bond. It is involved in an array of important biological processes during growth and development, reproduction and stress responses in plant. S-acylation is a ubiquitous mechanism in eukaryotes catalyzed by a family of enzymes called Protein S-Acyl Transferases (PATs). Since the discovery of the first PAT in yeast in 2002 research in S-acylation has accelerated in the mammalian system and followed by in plant. However, it is still a difficult field to study due to the large number of PATs and even larger number of putative S-acylated substrate proteins they modify in each genome. This is coupled with drawbacks in the techniques used to study S-acylation, leading to the slower progress in this field compared to protein phosphorylation, for example. In this review we will summarize the discoveries made so far based on knowledge learnt from the characterization of protein S-acyltransferases and the S-acylated proteins, the interaction mechanisms between PAT and its specific substrate protein(s) in yeast and mammals. Research in protein S-acylation and PATs in plants will also be covered although this area is currently less well studied in yeast and mammalian systems.

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“…Although it has been shown before that overexpressed HA is efficiently and completely acylated even upon introduction of mutations and truncations (Brett et al ., ), we performed radioactive palmitic acid labelling, revealing that Δ1 is indeed palmitoylated as well as the mutant wtC559S and wt, taken as examples, whereas no palmitic acid band is visible for wtC3S mutant (Figure S5; Scolari et al ., ). Furthermore, we analysed the donor–acceptor ratio of our chimeric proteins and found that within different experiments, the relative level of expression of GPImCFP to the respective HA variant did not significantly vary (Fig.…”

Section: Resultsmentioning

confidence: 99%

Modulation of cell surface transport and lipid raft localization by the cytoplasmic tail of the influenza virus hemagglutinin

et al. 2015

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Viral glycoproteins are highly variable in their primary structure, but on the other hand feature a high functional conservation to fulfil their versatile tasks during the pathogenic life cycle. Typically, all protein domains are optimized in that indispensable functions can be assigned to small conserved motifs or even individual amino acids. The cytoplasmic tail of many viral spike proteins, although of particular relevance for the virus biology, is often only insufficiently characterized. Hemagglutinin (HA), the receptor-binding protein of the influenza virus comprises a short cytoplasmic tail of 13 amino acids that exhibits three highly conserved palmitoylation sites. However, the particular importance of these modifications and the tail in general for intracellular trafficking and lateral membrane organization remains elusive. In this study, we generated HA core proteins consisting of transmembrane domain, cytoplasmic tail and a minor part of the ectodomain, tagged with a yellow fluorescent protein. Different mutation and truncation variants of these chimeric proteins were investigated using confocal microscopy, to characterize the role of cytoplasmic tail and palmitoylation for the intracellular trafficking to plasma membrane and Golgi apparatus. In addition, we assessed raft partitioning of the variants by Foerster resonance energy transfer with an established raft marker. We revealed a substantial influence of the cytoplasmic tail length on the intracellular distribution and surface exposure of the proteins. A complete removal of the tail hampers a physiological trafficking of the protein, whereas a partial truncation can be compensated by cytoplasmic palmitoylations. Plasma membrane raft partitioning on the other hand was found to imperatively require palmitoylations, and the cysteine at position 551 turned out to be of most relevance. Our data shed further light on the tight interconnection between cytoplasmic elements and intracellular trafficking and suggest a function of HA palmitoylations in both lateral sorting and anterograde trafficking of the glycoprotein.

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Site-specific S-Acylation of Influenza Virus Hemagglutinin

Cited by 46 publications

References 50 publications

Fatty acylation of proteins: The long and the short of it

Fatty acylation of proteins: The long and the short of it

Progress toward Understanding Protein S-acylation: Prospective in Plants

Modulation of cell surface transport and lipid raft localization by the cytoplasmic tail of the influenza virus hemagglutinin

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