Dataset Information

Protein palmitoylation: Palmitoyltransferases and their specificity.

ABSTRACT: A plethora of novel information has emerged over the past decade regarding protein lipidation. The reversible attachment of palmitic acid to cysteine residues, termed S-palmitoylation, has focused a special attention. This is mainly due to the unique role of this modification in the regulation of protein trafficking and function. A large family of protein acyltransferases (PATs) containing a conserved aspartate-histidine-histidine-cysteine motif use ping-pong kinetic mechanism to catalyze S-palmitoylation of a substrate protein. Here, we discuss the topology of PAT proteins and their cellular localization. We will also give an overview of the mechanism of protein palmitoylation and how it is regulated. New information concerning the recent discovery of depalmitoylating enzymes belonging to the family of ?/?-hydrolase domain-containing protein 17 (ABHD17A) is included. Considering the recent advances that have occurred in understanding the mechanisms underlying the interplay between palmitoylation and depalmitoylation, it is clear that we are beginning to understand the fundamental nature of how cellular signal-transduction mediates membrane-level organization in health and disease. Impact statement Protein palmitoylation is one of most important reversible post-translational modifications of protein function in cell-signaling systems. This review gathers the latest information on the molecular mechanism of protein palmitoyl transferase action. It also discusses the issue of substrate specificity of palmitoyl transferases. Another important question is the role of depalmitoylation enzymes. This review should help to formulate questions concerning the regulation of activity of particular PATs as well as of depalmitoylating enzymes (APT).

SUBMITTER: Tabaczar S

PROVIDER: S-EPMC5478004 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

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Protein palmitoylation: Palmitoyltransferases and their specificity.

Tabaczar Sabina S Czogalla Aleksander A Podkalicka Joanna J Biernatowska Agnieszka A Sikorski Aleksander F AF

Experimental biology and medicine (Maywood, N.J.) 20170509 11

A plethora of novel information has emerged over the past decade regarding protein lipidation. The reversible attachment of palmitic acid to cysteine residues, termed S-palmitoylation, has focused a special attention. This is mainly due to the unique role of this modification in the regulation of protein trafficking and function. A large family of protein acyltransferases (PATs) containing a conserved aspartate-histidine-histidine-cysteine motif use ping-pong kinetic mechanism to catalyze S-palm ...[more]

PMID: 28485685

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Project description:Many proteins are modified after their synthesis, by the addition of a lipid molecule to one or more cysteine residues, through a thioester bond. This modification is called S-acylation, and more commonly palmitoylation. This reaction is carried out by a family of enzymes, called palmitoyltransferases (PATs), characterized by the presence of a conserved 50- aminoacids domain called "Asp-His-His-Cys- Cysteine Rich Domain" (DHHC-CRD). There are 7 members of this family in the yeast Saccharomyces cerevisiae, and each of these proteins is thought to be responsible for the palmitoylation of a subset of substrates. Substrate specificity of PATs, however, is not yet fully understood. Several yeast PATs seem to have overlapping specificity, and it has been proposed that the machinery responsible for palmitoylating peripheral membrane proteins in mammalian cells, lacks specificity altogether.Here we investigate the specificity of transmembrane protein palmitoylation in S. cerevisiae, which is carried out predominantly by two PATs, Swf1 and Pfa4. We show that palmitoylation of transmembrane substrates requires dedicated PATs, since other yeast PATs are mostly unable to perform Swf1 or Pfa4 functions, even when overexpressed. Furthermore, we find that Swf1 is highly specific for its substrates, as it is unable to substitute for other PATs. To identify where Swf1 specificity lies, we carried out a bioinformatics survey to identify amino acids responsible for the determination of specificity or Specificity Determination Positions (SDPs) and showed experimentally, that mutation of the two best SDP candidates, A145 and K148, results in complete and partial loss of function, respectively. These residues are located within the conserved catalytic DHHC domain suggesting that it could also be involved in the determination of specificity. Finally, we show that modifying the position of the cysteines in Tlg1, a Swf1 substrate, results in lack of palmitoylation, as expected for a highly specific enzymatic reaction.

Dataset Information

Protein palmitoylation: Palmitoyltransferases and their specificity.

Publications

Protein palmitoylation: Palmitoyltransferases and their specificity.

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