Ghrelin octanoylation by ghrelin O-acyltransferase: Unique protein biochemistry underlying metabolic signaling

2019 ◽  
Vol 47 (1) ◽  
pp. 169-178 ◽  
Author(s):  
James L. Hougland
Keyword(s):  
Metabolic Regulation ◽  
Peptide Hormone ◽  
Acyl Donor ◽  
Post Translational Modification ◽  
Small Peptide ◽  
Protein Biochemistry ◽  
Physiological Processes ◽  
Unique Protein ◽  
The Status ◽  
Membrane Bound

Abstract Ghrelin is a small peptide hormone that requires a unique post-translational modification, serine octanoylation, to bind and activate the GHS-R1a receptor. Ghrelin signaling is implicated in a variety of neurological and physiological processes, but is most well known for its roles in controlling hunger and metabolic regulation. Ghrelin octanoylation is catalyzed by ghrelin O-acyltransferase (GOAT), a member of the membrane-bound O-acyltransferase (MBOAT) enzyme family. From the status of ghrelin as the only substrate for GOAT in the human genome to the source and requirement for the octanoyl acyl donor, the ghrelin–GOAT system is defined by multiple unique aspects within both protein biochemistry and endocrinology. In this review, we examine recent advances in our understanding of the interactions and mechanisms leading to ghrelin modification by GOAT, discuss the potential sources for the octanoyl acyl donor required for ghrelin's activation, and summarize the current landscape of molecules targeting ghrelin octanoylation through GOAT inhibition.

scholarly journals Ghrelin octanoylation by ghrelin O -acyltransferase: protein acylation impacting metabolic and neuroendocrine signalling

Open Biology ◽  
2021 ◽  
Vol 11 (7) ◽  
pp. 210080
Author(s):  
Tasha R. Davis ◽  
Mariah R. Pierce ◽  
Sadie X. Novak ◽  
James L. Hougland
Keyword(s):  
Metabolic Regulation ◽  
Energy Homeostasis ◽  
Structural Model ◽  
Peptide Hormone ◽  
Protein Biochemistry ◽  
Physiological Processes ◽  
Current State ◽  
Enzyme Superfamily ◽  
Wide Range ◽  
Membrane Bound

The acylated peptide hormone ghrelin impacts a wide range of physiological processes but is most well known for controlling hunger and metabolic regulation. Ghrelin requires a unique posttranslational modification, serine octanoylation, to bind and activate signalling through its cognate GHS-R1a receptor. Ghrelin acylation is catalysed by ghrelin O -acyltransferase (GOAT), a member of the membrane-bound O -acyltransferase (MBOAT) enzyme family. The ghrelin/GOAT/GHS-R1a system is defined by multiple unique aspects within both protein biochemistry and endocrinology. Ghrelin serves as the only substrate for GOAT within the human proteome and, among the multiple hormones involved in energy homeostasis and metabolism such as insulin and leptin, acts as the only known hormone in circulation that directly stimulates appetite and hunger signalling. Advances in GOAT enzymology, structural modelling and inhibitor development have revolutionized our understanding of this enzyme and offered new tools for investigating ghrelin signalling at the molecular and organismal levels. In this review, we briefly summarize the current state of knowledge regarding ghrelin signalling and ghrelin/GOAT enzymology, discuss the GOAT structural model in the context of recently reported MBOAT enzyme superfamily member structures, and highlight the growing complement of GOAT inhibitors that offer options for both ghrelin signalling studies and therapeutic applications.

scholarly journals Fatty acyl donor selectivity in membrane bound O-acyltransferases and communal cell fate decision-making

2015 ◽  
Vol 43 (2) ◽  
pp. 235-239 ◽  
Author(s):  
Rubina Tuladhar ◽  
Lawrence Lum
Keyword(s):  
Decision Making ◽  
Cell Fate ◽  
Protein Function ◽  
Cell Communication ◽  
Fatty Acyl ◽  
Acyl Donor ◽  
Cell Fate Decision ◽  
Post Translational Modification ◽  
Membrane Bound ◽  
Fate Decision

The post-translational modification of proteins with lipid moieties confers spatial and temporal control of protein function by restricting their subcellular distribution or movement in the extracellular milieu. Yet, little is known about the significance of lipid selectivity to the activity of proteins targeted for such modifications. Membrane bound O-acyl transferases (MBOATs) are a superfamily of multipass enzymes that transfer fatty acids on to lipid or protein substrates. Three MBOATs constitute a subfamily with secreted signalling molecules for substrates, the Wnt, Hedgehog (Hh) and Ghrelin proteins. Given their important roles in adult tissue homoeostasis, all three molecules and their respective associated acyltransferases provide a framework for interrogating the role of extracellular acylation events in cell-to-cell communication. Here, we discuss how the preference for a fatty acyl donor in the Wnt acyltransferase porcupine (Porcn) and possibly in other protein lipidation enzymes may provide a means for coupling metabolic health at the single cell level to communal cell fate decision-making in complex multicellular organisms.

scholarly journals PPARs as Metabolic Sensors and Therapeutic Targets in Liver Diseases

2021 ◽  
Vol 22 (15) ◽  
pp. 8298
Author(s):  
Hugo Christian Monroy-Ramirez ◽  
Marina Galicia-Moreno ◽  
Ana Sandoval-Rodriguez ◽  
Alejandra Meza-Rios ◽  
Arturo Santos ◽  
...  
Keyword(s):  
Liver Diseases ◽  
Metabolic Regulation ◽  
Structural Changes ◽  
Critical Role ◽  
The Body ◽  
Molecular Characteristics ◽  
Signal Pathways ◽  
Virus Infections ◽  
Physiological Processes ◽  
Hepatic Level

Carbohydrates and lipids are two components of the diet that provide the necessary energy to carry out various physiological processes to help maintain homeostasis in the body. However, when the metabolism of both biomolecules is altered, development of various liver diseases takes place; such as metabolic-associated fatty liver diseases (MAFLD), hepatitis B and C virus infections, alcoholic liver disease (ALD), and in more severe cases, hepatocelular carcinoma (HCC). On the other hand, PPARs are a family of ligand-dependent transcription factors with an important role in the regulation of metabolic processes to hepatic level as well as in other organs. After interaction with specific ligands, PPARs are translocated to the nucleus, undergoing structural changes to regulate gene transcription involved in lipid metabolism, adipogenesis, inflammation and metabolic homeostasis. This review aims to provide updated data about PPARs’ critical role in liver metabolic regulation, and their involvement triggering the genesis of several liver diseases. Information is provided about their molecular characteristics, cell signal pathways, and the main pharmacological therapies that modulate their function, currently engaged in the clinic scenario, or in pharmacological development.

scholarly journals Aptamers selected against the unglycosylated EGFRvIII ectodomain and delivered intracellularly reduce membrane-bound EGFRvIII and induce apoptosis

2009 ◽  
Vol 390 (2) ◽  
pp. 137-144 ◽  
Author(s):  
Yingmiao Liu ◽  
Chien-Tsun Kuan ◽  
Jing Mi ◽  
Xiuwu Zhang ◽  
Bryan M. Clary ◽  
...  
Keyword(s):  
Growth Factor Receptor ◽  
Rna Aptamers ◽  
Normal Brain ◽  
Post Translational Modification ◽  
Expression And Purification ◽  
Post Translational Modifications ◽  
Protein Expression And Purification ◽  
Epidermal Growth ◽  
Membrane Bound

Abstract Epidermal growth factor receptor variant III (EGFRvIII) is a glycoprotein uniquely expressed in glioblastoma, but not in normal brain tissues. To develop targeted therapies for brain tumors, we selected RNA aptamers against the histidine-tagged EGFRvIII ectodomain, using an Escherichia coli system for protein expression and purification. Representative aptamer E21 has a dissociation constant (Kd) of 33×10-9 m, and exhibits high affinity and specificity for EGFRvIII in ELISA and surface plasmon resonance assays. However, selected aptamers cannot bind the same protein expressed from eukaryotic cells because glycosylation, a post-translational modification present only in eukaryotic systems, significantly alters the structure of the target protein. By transfecting EGFRvIII aptamers into cells, we find that membrane-bound, glycosylated EGFRvIII is reduced and the percentage of cells undergoing apoptosis is increased. We postulate that transfected aptamers can interact with newly synthesized EGFRvIII, disrupt proper glycosylation, and reduce the amount of mature EGFRvIII reaching the cell surface. Our work establishes the feasibility of disrupting protein post-translational modifications in situ with aptamers. This finding is useful for elucidating the function of proteins of interest with various modifications, as well as dissecting signal transduction pathways.

scholarly journals Deimination, Intermediate Filaments and Associated Proteins

2020 ◽  
Vol 21 (22) ◽  
pp. 8746
Author(s):  
Julie Briot ◽  
Michel Simon ◽  
Marie-Claire Méchin
Keyword(s):  
Rheumatoid Arthritis ◽  
Multiple Sclerosis ◽  
Cell Differentiation ◽  
Intermediate Filaments ◽  
Cross Linking ◽  
Post Translational Modification ◽  
Innate And Adaptive Immunity ◽  
Calcium Dependent ◽  
Physiological Processes ◽  
Associated Proteins

Deimination (or citrullination) is a post-translational modification catalyzed by a calcium-dependent enzyme family of five peptidylarginine deiminases (PADs). Deimination is involved in physiological processes (cell differentiation, embryogenesis, innate and adaptive immunity, etc.) and in autoimmune diseases (rheumatoid arthritis, multiple sclerosis and lupus), cancers and neurodegenerative diseases. Intermediate filaments (IF) and associated proteins (IFAP) are major substrates of PADs. Here, we focus on the effects of deimination on the polymerization and solubility properties of IF proteins and on the proteolysis and cross-linking of IFAP, to finally expose some features of interest and some limitations of citrullinomes.

scholarly journals Colocalization of ghrelin O-acyltransferase and ghrelin in gastric mucosal cells

2009 ◽  
Vol 297 (1) ◽  
pp. E134-E141 ◽  
Author(s):  
Ichiro Sakata ◽  
Jing Yang ◽  
Charlotte E. Lee ◽  
Sherri Osborne-Lawrence ◽  
Sherry A. Rovinsky ◽  
...  
Keyword(s):  
Peptide Hormone ◽  
Whole Body ◽  
Histochemical Analysis ◽  
Oxyntic Mucosa ◽  
Body Distribution ◽  
Naturally Occurring ◽  
Mucosal Cells ◽  
Membrane Bound ◽  
High Degree ◽  
Dual Label

Ghrelin is a peptide hormone with many known functions, including orexigenic, blood glucose-regulatory, and antidepressant actions, among others. Mature ghrelin is unique in that it is the only known naturally occurring peptide to be posttranslationally modified by O-acylation with octanoate. This acylation is required for many of ghrelin's actions, including its effects on promoting increases in food intake and body weight. GOAT (ghrelin O-acyltransferase), one of 16 members of the MBOAT family of membrane-bound O-acyltransferases, has recently been identified as the enzyme responsible for catalyzing the addition of the octanoyl group to ghrelin. Although the initial reports of GOAT have localized its encoding mRNA to tissues known to contain ghrelin, it is as yet unclear whether the octanoylation occurs within ghrelin-producing cells or in neighboring cells. Here, we have performed dual-label histochemical analysis on mouse stomach sections and quantitative PCR on mRNAs from highly enriched pools of mouse gastric ghrelin cells to demonstrate a high degree of GOAT mRNA expression within ghrelin-producing cells of the gastric oxyntic mucosa. We also demonstrate that GOAT is the only member of the MBOAT family whose expression is highly enriched within gastric ghrelin cells and whose whole body distribution mirrors that of ghrelin.

scholarly journals Neutrophil azurophilic granule glycoproteins are distinctively decorated by atypical pauci- and phosphomannose glycans

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Karli R. Reiding ◽  
Yu-Hsien Lin ◽  
Floris P. J. van Alphen ◽  
Alexander B. Meijer ◽  
Albert J. R. Heck
Keyword(s):  
Immune System ◽  
Autoimmune Disease ◽  
Secreted Proteins ◽  
Receptor Interaction ◽  
Post Translational Modification ◽  
Site Specific ◽  
Healthy Donors ◽  
Asymmetric Hybrid ◽  
Membrane Bound ◽  
High Mannose

AbstractWhile neutrophils are critical first-responders of the immune system, they also cause tissue damage and act in a variety of autoimmune diseases. Many neutrophil proteins are N-glycosylated, a post-translational modification that may affect, among others, enzymatic activity, receptor interaction, and protein backbone accessibility. So far, a handful neutrophil proteins were reported to be decorated with atypical small glycans (paucimannose and smaller) and phosphomannosylated glycans. To elucidate the occurrence of these atypical glycoforms across the neutrophil proteome, we performed LC-MS/MS-based (glyco)proteomics of pooled neutrophils from healthy donors, obtaining site-specific N-glycan characterisation of >200 glycoproteins. We found that glycoproteins that are typically membrane-bound to be mostly decorated with high-mannose/complex N-glycans, while secreted proteins mainly harboured complex N-glycans. In contrast, proteins inferred to originate from azurophilic granules carried distinct and abundant paucimannosylation, asymmetric/hybrid glycans, and glycan phosphomannosylation. As these same proteins are often autoantigenic, uncovering their atypical glycosylation characteristics is an important step towards understanding autoimmune disease and improving treatment.

scholarly journals The physiology, pathology and potential therapeutic application of serotonylation

2021 ◽  
Vol 134 (11) ◽  
Author(s):  
Shu-Heng Jiang ◽  
Ya-Hui Wang ◽  
Li-Peng Hu ◽  
Xu Wang ◽  
Jun Li ◽  
...  
Keyword(s):  
Matrix Protein ◽  
Small Gtpases ◽  
Cytoskeletal Proteins ◽  
Extracellular Matrix Protein ◽  
Post Translational Modification ◽  
Pharmacological Interventions ◽  
Therapeutic Application ◽  
Disease Treatment ◽  
Physiological Processes ◽  
Potential Therapeutic Application

ABSTRACT The classical neurotransmitter serotonin or 5-hydroxytryptamine (5-HT), synthesized from tryptophan, can be produced both centrally and peripherally. Through binding to functionally distinct receptors, serotonin is profoundly implicated in a number of fundamental physiological processes and pathogenic conditions. Recently, serotonin has been found covalently incorporated into proteins, a newly identified post-translational modification termed serotonylation. Transglutaminases (TGMs), especially TGM2, are responsible for catalyzing the transamidation reaction by transferring serotonin to the glutamine residues of target proteins. Small GTPases, extracellular matrix protein fibronectin, cytoskeletal proteins and histones are the most reported substrates for serotonylation, and their functions are triggered by this post-translational modification. This Review highlights the roles of serotonylation in physiology and diseases and provides perspectives for pharmacological interventions to ameliorate serotonylation for disease treatment.

rasp, a putative transmembrane acyltransferase, is required for Hedgehog signaling

Development ◽  
2002 ◽  
Vol 129 (4) ◽  
pp. 843-851 ◽  
Author(s):  
Craig A. Micchelli ◽  
Inge The ◽  
Erica Selva ◽  
Vladic Mogila ◽  
Norbert Perrimon
Keyword(s):  
Hedgehog Signaling ◽  
Transmembrane Protein ◽  
Post Translational Modification ◽  
Protein Levels ◽  
Lethal Mutations ◽  
Segment Polarity ◽  
Invertebrate Development ◽  
Membrane Bound ◽  
Segment Polarity Gene ◽  
Polarity Gene

Members of the Hedgehog (Hh) family encode secreted molecules that act as potent organizers during vertebrate and invertebrate development. Post-translational modification regulates both the range and efficacy of Hh protein. One such modification is the acylation of the N-terminal cysteine of Hh. In a screen for zygotic lethal mutations associated with maternal effects, we have identified rasp, a novel Drosophila segment polarity gene. Analysis of the rasp mutant phenotype, in both the embryo and wing imaginal disc demonstrates that rasp does not disrupt Wnt/Wingless signaling but is specifically required for Hh signaling. The requirement of rasp is restricted only to those cells that produce Hh; hh transcription, protein levels and distribution are not affected by the loss of rasp. Molecular analysis reveals that rasp encodes a multipass transmembrane protein that has homology to a family of membrane bound O-acyl transferases. Our results suggest that Rasp-dependent acylation is necessary to generate a fully active Hh protein.

Sign in / Sign up

Export Citation Format

Share Document