Mechanism and function of DHHC S-acyltransferases

2013 ◽  
Vol 41 (1) ◽  
pp. 29-34 ◽  
Author(s):  
Maurine E. Linder ◽  
Benjamin C. Jennings
Keyword(s):  
Fatty Acids ◽  
Protein S ◽  
Enzyme Mechanism ◽  
Long Chain Fatty Acids ◽  
Post Translational Modification ◽  
Rich Domain ◽  
Cytoplasmic Face ◽  
Protein Membrane ◽  
And Function ◽  
Cysteine Rich Domain

Protein S-palmitoylation is a reversible post-translational modification of proteins with fatty acids. In the last 5 years, improved proteomic methods have increased the number of proteins identified as substrates for palmitoylation from tens to hundreds. Palmitoylation regulates protein membrane interactions, activity, trafficking and stability and can be constitutive or regulated by signalling inputs. A family of PATs (protein acyltransferases) is responsible for modifying proteins with palmitate or other long-chain fatty acids on the cytoplasmic face of cellular membranes. PATs share a signature DHHC (Asp-His-His-Cys) cysteine-rich domain that is the catalytic centre of the enzyme. The biomedical importance of members of this family is underscored by their association with intellectual disability, Huntington's disease and cancer in humans, and raises the possibility of DHHC PATs as targets for therapeutic intervention. In the present paper, we discuss recent progress in understanding enzyme mechanism, regulation and substrate specificity.

scholarly journals Structure and function of the ROR2 cysteine-rich domain in vertebrate noncanonical WNT5A signaling

2021 ◽  
Author(s):  
Samuel C Griffiths ◽  
Jia Tan ◽  
Armin Wagner ◽  
Levi L Blazer ◽  
Jarret J Adams ◽  
...  
Keyword(s):  
Receptor Tyrosine Kinase ◽  
Structure And Function ◽  
Hydrophobic Pocket ◽  
Rich Domain ◽  
Frizzled Receptors ◽  
Receptor Action ◽  
Robinow Syndrome ◽  
Modified Proteins ◽  
And Function ◽  
Cysteine Rich Domain

The receptor tyrosine kinase ROR2 mediates noncanonical WNT5A signaling to orchestrate tissue morphogenetic processes, and dysfunction of the pathway causes Robinow syndrome, Brachydactyly B and metastatic diseases. The domain(s) and mechanisms required for ROR2 function, however, remain unclear. We solved the crystal structure of the extracellular cysteine rich (CRD) and Kringle (Kr) domains of ROR2 and found that, unlike other CRDs, the ROR2 CRD lacks the signature hydrophobic pocket that binds lipids/lipid-modified proteins, such as WNTs, suggesting a novel mechanism of receptor action. Functionally, we showed that the ROR2 CRD, but not other domains, is required and minimally sufficient to promote WNT5A signaling, and Robinow mutations in the CRD and the adjacent Kr alter ROR2 function. Moreover, we demonstrated that the activity of the ROR2 CRD requires Frizzled receptors. Thus, ROR2 acts via its CRD to potentiate the function of a receptor supercomplex that includes Frizzleds to transduce WNT5A signals.

scholarly journals Very long-chain fatty acids support synaptic structure and function in the mammalian retina

OCL ◽  
2015 ◽  
Vol 23 (1) ◽  
pp. D113 ◽  
Author(s):  
Blake R. Hopiavuori ◽  
Lea D. Bennett ◽  
Richard S. Brush ◽  
Matthew J. Van Hook ◽  
Wallace B. Thoreson ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Structure And Function ◽  
Long Chain Fatty Acids ◽  
Synaptic Structure ◽  
Mammalian Retina ◽  
And Function ◽  
Long Chain ◽  
Chain Fatty Acids

scholarly journals An atlas of Arabidopsis protein S-Acylation reveals its widespread role in plant cell organisation of and function

2020 ◽  
Author(s):  
Manoj Kumar ◽  
Paul Carr ◽  
Simon Turner
Keyword(s):  
Sequence Similarity ◽  
Protein S ◽  
Cysteine Residue ◽  
Cellulose Synthesis ◽  
Post Translational Modification ◽  
Cellular Functions ◽  
Ring Type ◽  
Arabidopsis Proteome ◽  
Arabidopsis Protein ◽  
And Function

AbstractS-acylation is the addition of a fatty acid to a cysteine residue of a protein. While this modification may profoundly alter protein behaviour, its effects on the function of plant proteins remains poorly characterised, largely as a result to the lack of basic information regarding which proteins are S-acylated and where in the proteins the modification occurs. In order to address this gap in our knowledge, we have performed a comprehensive analysis of plant protein S-acylation from 6 separate tissues. In our highest confidence group, we identified 5185 cysteines modified by S-acylation, which were located in 4891 unique peptides from 2643 different proteins. This represents around 9% of the entire Arabidopsis proteome and suggests an important role for S-acylation in many essential cellular functions including trafficking, signalling and metabolism. To illustrate the potential of this dataset, we focus on cellulose synthesis and confirm for the first time the S-acylation of all proteins known to be involved in cellulose synthesis and trafficking of the cellulose synthase complex. In the secondary cell walls, cellulose synthesis requires three different catalytic subunits (CESA4, CESA7 and CESA8) that all exhibit striking sequence similarity. While all three proteins have been widely predicted to possess a RING-type zinc finger at their N-terminus, for CESA4 and CESA8, we find evidence for S-acylation of cysteines in this region that is incompatible with any role in coordinating metal ions. We show that while CESA7 may possess a RING type domain, the same region of CESA4 and CESA8 appear to have evolved a very different structure. Together, the data suggests this study represents an atlas of S-acylation in Arabidopsis that will facilitate the broader study of this elusive post-translational modification in plants as well as demonstrates the importance of undertaking further work in this area.

Zinc co-ordination by the DHHC cysteine-rich domain of the palmitoyltransferase Swf1

2013 ◽  
Vol 454 (3) ◽  
pp. 427-435 ◽  
Author(s):  
Ayelén González Montoro ◽  
Rodrigo Quiroga ◽  
Javier Valdez Taubas
Keyword(s):  
Amino Acids ◽  
Tertiary Structure ◽  
Random Mutagenesis ◽  
Binding Pocket ◽  
Essential Amino Acids ◽  
Zinc Binding ◽  
Loss Of Function ◽  
Post Translational Modification ◽  
Rich Domain ◽  
Cysteine Rich Domain

S-acylation, commonly known as palmitoylation, is a widespread post-translational modification of proteins that consists of the thioesterification of one or more cysteine residues with fatty acids. This modification is catalysed by a family of PATs (palmitoyltransferases), characterized by the presence of a 50-residue long DHHC-CRD (Asp-His-His-Cys cysteine-rich domain). To gain knowledge on the structure–function relationships of these proteins, we carried out a random-mutagenesis assay designed to uncover essential amino acids in Swf1, the yeast PAT responsible for the palmitoylation of SNARE (soluble N-ethylmaleimide-sensitive fusion protein-attachment protein receptor) proteins. We identified 21 novel loss-of-function mutations, which are mostly localized within the DHHC-CRD. Modelling of the tertiary structure of the Swf1 DHHC domain suggests that it could fold as a zinc-finger domain, co-ordinating two zinc atoms in a CCHC arrangement. All residues predicted to be involved in the co-ordination of zinc were found to be essential for Swf1 function in the screen. Moreover, these mutations result in unstable proteins, in agreement with a structural role for these zinc fingers. The conservation of amino acids predicted to form each zinc-binding pocket suggests a shared function, as the selective pressure to maintain them is lost upon mutation of one of them. A Swf1 orthologue that lacks one of the zinc-binding pockets is able to complement a yeast swf1∆ strain, possibly because a similar fold can be stabilized by hydrogen bonds instead of zinc co-ordination. Finally, we show directly that recombinant Swf1 DHHC-CRD is able to bind zinc. Sequence analyses of DHHC domains allowed us to present models of the zinc-binding properties for all PATs.

scholarly journals Substrate recruitment by zDHHC protein acyltransferases

Open Biology ◽  
2021 ◽  
Vol 11 (4) ◽  
Author(s):  
Martin Ian P. Malgapo ◽  
Maurine E. Linder
Keyword(s):  
Fatty Acids ◽  
Intellectual Disability ◽  
Membrane Proteins ◽  
Cysteine Residue ◽  
Integral Membrane Proteins ◽  
Multigene Families ◽  
Protein Substrates ◽  
Rich Domain ◽  
Protein Palmitoylation ◽  
Cysteine Rich Domain

Protein palmitoylation is the post-translational attachment of fatty acids, most commonly palmitate (C16 : 0), onto a cysteine residue of a protein. This reaction is catalysed by a family of integral membrane proteins, the zDHHC protein acyltransferases (PATs), so-called due to the presence of an invariant Asp–His–His–Cys (DHHC) cysteine-rich domain harbouring the catalytic centre of the enzyme. Conserved throughout eukaryotes, the zDHHC PATs are encoded by multigene families and mediate palmitoylation of thousands of protein substrates. In humans, a number of zDHHC proteins are associated with human diseases, including intellectual disability, Huntington's disease, schizophrenia and cancer. Key to understanding the physiological and pathophysiological importance of individual zDHHC proteins is the identification of their protein substrates. Here, we will describe the approaches and challenges in assigning substrates for individual zDHHCs, highlighting key mechanisms that underlie substrate recruitment.

Palmitoylation and palmitoyl-transferases in Plasmodium parasites

2015 ◽  
Vol 43 (2) ◽  
pp. 240-245 ◽  
Author(s):  
Nicola Hodson ◽  
Brandon Invergo ◽  
Julian C. Rayner ◽  
Jyoti S. Choudhary
Keyword(s):  
Protein Localization ◽  
Protein S ◽  
Transferase Activity ◽  
Post Translational Modifications ◽  
Rich Domain ◽  
Molecular Events ◽  
Reversible Modification ◽  
Species Specific ◽  
Cellular Compartments ◽  
Cysteine Rich Domain

Protein post-translational modifications (PTM) are commonly used to regulate biological processes. Protein S-acylation is an enzymatically regulated reversible modification that has been shown to modulate protein localization, activity and membrane binding. Proteome-scale discovery on Plasmodium falciparum schizonts has revealed a complement of more than 400 palmitoylated proteins, including those essential for host invasion and drug resistance. The wide regulatory affect on this species is endorsed by the presence of 12 proteins containing the conserved DHHC–CRD (DHHC motif within a cysteine-rich domain) that is associated with palmitoyl-transferase activity. Genetic interrogation of these enzymes in Apicomplexa has revealed essentiality and distinct localization at cellular compartments; these features are species specific and are not observed in yeast. It is clear that palmitoylation has an elaborate role in Plasmodium biology and opens intriguing questions on the functional consequence of this group of acylation modifications and how the protein S-acyl transferases (PATs) orchestrate molecular events.

Structure and function of DHHC protein S-acyltransferases

2017 ◽  
Vol 45 (4) ◽  
pp. 923-928 ◽  
Author(s):  
Colin D. Gottlieb ◽  
Maurine E. Linder
Keyword(s):  
Mouse Models ◽  
Protein Function ◽  
Molecular Mechanisms ◽  
Protein S ◽  
Structure And Function ◽  
Deficient Mouse ◽  
Enzymatic Function ◽  
Cytoplasmic Face ◽  
Dhhc Protein ◽  
And Function

It has been estimated that 10% of the human genome encodes proteins that are fatty acylated at cysteine residues. The vast majority of these proteins are modified by members of the DHHC protein family, which carry out their enzymatic function on the cytoplasmic face of cell membranes. The biomedical importance of DHHC proteins is underscored by their association with human disease; unique and essential roles for DHHC proteins have been uncovered using DHHC-deficient mouse models. Accordingly, there is great interest in elucidating the molecular mechanisms that underlie DHHC protein function. In this review, we present recent insights into the structure and function of DHHC enzymes.

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