Protein palmitoylation: Palmitoyltransferases and their specificity

There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

Abstract

<p class="first" id="d2632478e115">A plethora of novel information has emerged over the past decade regarding protein lipidation. The reversible attachment of palmitic acid to cysteine residues, termed <i>S</i>-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 <i>S</i>-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 α/β-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. </p><div class="section"> <a class="named-anchor" id="sec1-1535370217707732">  </a> <h5 class="section-title" id="d2632478e124">Impact statement</h5> <p id="d2632478e126">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). </p> </div>

Related collections

Most cited references 59

Record: found
Abstract: found
Article: not found

Ankyrin repeat: a unique motif mediating protein-protein interactions.

Junan Li, Anjali Mahajan, Ming-Daw Tsai (2006)

Ankyrin repeat, one of the most widely existing protein motifs in nature, consists of 30-34 amino acid residues and exclusively functions to mediate protein-protein interactions, some of which are directly involved in the development of human cancer and other diseases. Each ankyrin repeat exhibits a helix-turn-helix conformation, and strings of such tandem repeats are packed in a nearly linear array to form helix-turn-helix bundles with relatively flexible loops. The global structure of an ankyrin repeat protein is mainly stabilized by intra- and inter-repeat hydrophobic and hydrogen bonding interactions. The repetitive and elongated nature of ankyrin repeat proteins provides the molecular bases of the unique characteristics of ankyrin repeat proteins in protein stability, folding and unfolding, and binding specificity. Recent studies have demonstrated that ankyrin repeat proteins do not recognize specific sequences, and interacting residues are discontinuously dispersed into the whole molecules of both the ankyrin repeat protein and its partner. In addition, the availability of thousands of ankyrin repeat sequences has made it feasible to use rational design to modify the specificity and stability of physiologically important ankyrin repeat proteins and even to generate ankyrin repeat proteins with novel functions through combinatorial chemistry approaches.

0 comments Cited 183 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: not found

The palmitoylation machinery is a spatially organizing system for peripheral membrane proteins.

Oliver Rocks, Marc Gerauer, Nachiket Vartak … (2010)

Reversible S-palmitoylation of cysteine residues critically controls transient membrane tethering of peripheral membrane proteins. Little is known about how the palmitoylation machinery governs their defined localization and function. We monitored the spatially resolved reaction dynamics and substrate specificity of the core mammalian palmitoylation machinery using semisynthetic substrates. Palmitoylation is detectable only on the Golgi, whereas depalmitoylation occurs everywhere in the cell. The reactions are not stereoselective and lack any primary consensus sequence, demonstrating that substrate specificity is not essential for de-/repalmitoylation. Both palmitate attachment and removal require seconds to accomplish. This reaction topography and rapid kinetics allows the continuous redirection of mislocalized proteins via the post-Golgi sorting apparatus. Unidirectional secretion ensures the maintenance of a proper steady-state protein distribution between the Golgi and the plasma membrane, which are continuous with endosomes. This generic spatially organizing system differs from conventional receptor-mediated targeting mechanisms and efficiently counteracts entropy-driven redistribution of palmitoylated peripheral membrane proteins over all membranes. 2010 Elsevier Inc. All rights reserved.

0 comments Cited 120 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: not found

Small-molecule inhibition of APT1 affects Ras localization and signaling.

Stefan Wetzel, Oliver Rocks, Luc Brunsveld … (2010)

Cycles of depalmitoylation and repalmitoylation critically control the steady-state localization and function of various peripheral membrane proteins, such as Ras proto-oncogene products. Interference with acylation using small molecules is a strategy to modulate cellular localization--and thereby unregulated signaling--caused by palmitoylated Ras proteins. We present the knowledge-based development and characterization of a potent inhibitor of acyl protein thioesterase 1 (APT1), a bona fide depalmitoylating enzyme that is, so far, poorly characterized in cells. The inhibitor, palmostatin B, perturbs the cellular acylation cycle at the level of depalmitoylation and thereby causes a loss of the precise steady-state localization of palmitoylated Ras. As a consequence, palmostatin B induces partial phenotypic reversion in oncogenic HRasG12V-transformed fibroblasts. We identify APT1 as one of the thioesterases in the acylation cycle and show that this protein is a cellular target of the inhibitor.