Regulation of the water channel aquaporin-2 by posttranslational modification

2011 ◽  
Vol 300 (5) ◽  
pp. F1062-F1073 ◽  
Author(s):  
Hanne B. Moeller ◽  
Emma T. B. Olesen ◽  
Robert A. Fenton
Keyword(s):  
Membrane Proteins ◽  
Protein Interactions ◽  
Posttranslational Modifications ◽  
Posttranslational Modification ◽  
Water Channel ◽  
Cellular Functions ◽  
Aquaporin 2 ◽  
Eukaryotic Membrane Proteins ◽  
Insight Into

The cellular functions of many eukaryotic membrane proteins, including the vasopressin-regulated water channel aquaporin-2 (AQP2), are regulated by posttranslational modifications. In this article, we discuss the experimental discoveries that have advanced our understanding of how posttranslational modifications affect AQP2 function, especially as they relate to the role of AQP2 in the kidney. We review the most recent data demonstrating that glycosylation and, in particular, phosphorylation and ubiquitination are mechanisms that regulate AQP2 activity, subcellular sorting and distribution, degradation, and protein interactions. From a clinical perspective, posttranslational modification resulting in protein misrouting or degradation may explain certain forms of nephrogenic diabetes insipidus. In addition to providing major insight into the function and dynamics of renal AQP2 regulation, the analysis of AQP2 posttranslational modification may provide general clues as to the role of posttranslational modification for regulation of other membrane proteins.

Advances in aquaporin-2 trafficking mechanisms and their implications for treatment of water balance disorders

2020 ◽  
Vol 319 (1) ◽  
pp. C1-C10 ◽  
Author(s):  
Robert A. Fenton ◽  
Sathish K. Murali ◽  
Hanne B. Moeller
Keyword(s):  
Protein Interactions ◽  
Collecting Duct ◽  
Water Channel ◽  
Plasma Osmolality ◽  
Carboxyl Terminus ◽  
Apical Plasma Membrane ◽  
Tail Domain ◽  
Water Reabsorption ◽  
Aquaporin 2

In mammals, conservation of body water is critical for survival and is dependent on the kidneys’ ability to minimize water loss in the urine during periods of water deprivation. The collecting duct water channel aquaporin-2 (AQP2) plays an essential role in this homeostatic response by facilitating water reabsorption along osmotic gradients. The ability to increase the levels of AQP2 in the apical plasma membrane following an increase in plasma osmolality is a rate-limiting step in water reabsorption, a process that is tightly regulated by the antidiuretic hormone arginine vasopressin (AVP). In this review, the focus is on the role of the carboxyl-terminus of AQP2 as a key regulatory point for AQP2 trafficking. We provide an overview of AQP2 structure, disease-causing mutations in the AQP2 carboxyl-terminus, the role of posttranslational modifications such as phosphorylation and ubiquitylation in the tail domain, and their implications for balanced trafficking of AQP2. Finally, we discuss how various modifications of the AQP2 tail facilitate selective protein-protein interactions that modulate the AQP2 trafficking mechanism.

scholarly journals The intracellular dynamic of protein palmitoylation

2010 ◽  
Vol 191 (7) ◽  
pp. 1229-1238 ◽  
Author(s):  
Christine Salaun ◽  
Jennifer Greaves ◽  
Luke H. Chamberlain
Keyword(s):  
Posttranslational Modifications ◽  
Posttranslational Modification ◽  
Mammalian Cells ◽  
Protein Functionality ◽  
Peripheral Membrane Proteins ◽  
Protein Palmitoylation ◽  
Thioester Bond ◽  
Intracellular Sorting ◽  
Intracellular Dynamic ◽  
Insight Into

S-palmitoylation describes the reversible attachment of fatty acids (predominantly palmitate) onto cysteine residues via a labile thioester bond. This posttranslational modification impacts protein functionality by regulating membrane interactions, intracellular sorting, stability, and membrane micropatterning. Several recent findings have provided a tantalizing insight into the regulation and spatiotemporal dynamics of protein palmitoylation. In mammalian cells, the Golgi has emerged as a possible super-reaction center for the palmitoylation of peripheral membrane proteins, whereas palmitoylation reactions on post-Golgi compartments contribute to the regulation of specific substrates. In addition to palmitoylating and depalmitoylating enzymes, intracellular palmitoylation dynamics may also be controlled through interplay with distinct posttranslational modifications, such as phosphorylation and nitrosylation.

scholarly journals The Role of Posttranslational Modifications in DNA Repair

2020 ◽  
Vol 2020 ◽  
pp. 1-13
Author(s):  
Miaomiao Bai ◽  
Dongdong Ti ◽  
Qian Mei ◽  
Jiejie Liu ◽  
Xin Yan ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Protein Interactions ◽  
Posttranslational Modifications ◽  
Genome Stability ◽  
Protein Localization ◽  
Complex Structure ◽  
Protein Protein Interactions ◽  
Regulate Protein

The human body is a complex structure of cells, which are exposed to many types of stress. Cells must utilize various mechanisms to protect their DNA from damage caused by metabolic and external sources to maintain genomic integrity and homeostasis and to prevent the development of cancer. DNA damage inevitably occurs regardless of physiological or abnormal conditions. In response to DNA damage, signaling pathways are activated to repair the damaged DNA or to induce cell apoptosis. During the process, posttranslational modifications (PTMs) can be used to modulate enzymatic activities and regulate protein stability, protein localization, and protein-protein interactions. Thus, PTMs in DNA repair should be studied. In this review, we will focus on the current understanding of the phosphorylation, poly(ADP-ribosyl)ation, ubiquitination, SUMOylation, acetylation, and methylation of six typical PTMs and summarize PTMs of the key proteins in DNA repair, providing important insight into the role of PTMs in the maintenance of genome stability and contributing to reveal new and selective therapeutic approaches to target cancers.

scholarly journals Histone H3K23-specific acetylation by MORF is coupled to H3K14 acylation

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Brianna J. Klein ◽  
Suk Min Jang ◽  
Catherine Lachance ◽  
Wenyi Mi ◽  
Jie Lyu ◽  
...  
Keyword(s):  
Posttranslational Modification ◽  
Memory Impairment ◽  
Target Genes ◽  
Epigenetic Mark ◽  
Mechanistic Insight ◽  
Genomic Analyses ◽  
Insight Into

Abstract Acetylation of histone H3K23 has emerged as an essential posttranslational modification associated with cancer and learning and memory impairment, yet our understanding of this epigenetic mark remains insufficient. Here, we identify the native MORF complex as a histone H3K23-specific acetyltransferase and elucidate its mechanism of action. The acetyltransferase function of the catalytic MORF subunit is positively regulated by the DPF domain of MORF (MORFDPF). The crystal structure of MORFDPF in complex with crotonylated H3K14 peptide provides mechanistic insight into selectivity of this epigenetic reader and its ability to recognize both histone and DNA. ChIP data reveal the role of MORFDPF in MORF-dependent H3K23 acetylation of target genes. Mass spectrometry, biochemical and genomic analyses show co-existence of the H3K23ac and H3K14ac modifications in vitro and co-occupancy of the MORF complex, H3K23ac, and H3K14ac at specific loci in vivo. Our findings suggest a model in which interaction of MORFDPF with acylated H3K14 promotes acetylation of H3K23 by the native MORF complex to activate transcription.

Insight into factors directing high production of eukaryotic membrane proteins; production of 13 human AQPs inPichia pastoris

2009 ◽  
Vol 26 (4) ◽  
pp. 215-227 ◽  
Author(s):  
Fredrik Öberg ◽  
Mikael Ekvall ◽  
Maria Nyblom ◽  
Fredrik Öberg ◽  
Mikael Ekvall ◽  
...  
Keyword(s):  
Membrane Proteins ◽  
High Production ◽  
Eukaryotic Membrane Proteins ◽  
Insight Into

scholarly journals Getting into position: the catalytic mechanisms of protein ubiquitylation

2004 ◽  
Vol 379 (3) ◽  
pp. 513-525 ◽  
Author(s):  
Lori A. PASSMORE ◽  
David BARFORD
Keyword(s):  
Protein Interactions ◽  
Regulatory Elements ◽  
Substrate Selection ◽  
Protein Protein Interactions ◽  
Different Types ◽  
Catalytic Mechanisms ◽  
Cellular Pathways ◽  
Ubiquitin Conjugating Enzymes ◽  
Insight Into

The role of protein ubiquitylation in the control of diverse cellular pathways has recently gained widespread attention. Ubiquitylation not only directs the targeted destruction of tagged proteins by the 26 S proteasome, but it also modulates protein activities, protein–protein interactions and subcellular localization. An understanding of the components involved in protein ubiquitylation (E1s, E2s and E3s) is essential to understand how specificity and regulation are conferred upon these pathways. Much of what we know about the catalytic mechanisms of protein ubiquitylation comes from structural studies of the proteins involved in this process. Indeed, structures of ubiquitin-activating enzymes (E1s) and ubiquitin-conjugating enzymes (E2s) have provided insight into their mechanistic details. E3s (ubiquitin ligases) contain most of the substrate specificity and regulatory elements required for protein ubiquitylation. Although several E3 structures are available, the specific mechanistic role of E3s is still unclear. This review will discuss the different types of ubiquitin signals and how they are generated. Recent advances in the field of protein ubiquitylation will be examined, including the mechanisms of E1, E2 and E3. In particular, we discuss the complexity of molecular recognition required to impose selectivity on substrate selection and topology of poly-ubiquitin chains.

scholarly journals The Role of Posttranslational Modification and Mitochondrial Quality Control in Cardiovascular Diseases

2021 ◽  
Vol 2021 ◽  
pp. 1-15
Author(s):  
Jinlin Liu ◽  
Li Zhong ◽  
Rui Guo
Keyword(s):  
Quality Control ◽  
Posttranslational Modifications ◽  
Posttranslational Modification ◽  
Protein Function ◽  
Therapeutic Potential ◽  
Normal Function ◽  
Future Research ◽  
Mitochondrial Quality Control ◽  
Mitochondrial Homeostasis

Cardiovascular disease (CVD) is the leading cause of death in the world. The mechanism behind CVDs has been studied for decades; however, the pathogenesis is still controversial. Mitochondrial homeostasis plays an essential role in maintaining the normal function of the cardiovascular system. The alterations of any protein function in mitochondria may induce abnormal mitochondrial quality control and unexpected mitochondrial dysfunction, leading to CVDs. Posttranslational modifications (PTMs) affect protein function by reversibly changing their conformation. This review summarizes how common and novel PTMs influence the development of CVDs by regulating mitochondrial quality control. It provides not only ideas for future research on the mechanism of some types of CVDs but also ideas for CVD treatments with therapeutic potential.

scholarly journals Aquaporin-2 membrane targeting: still a conundrum

2017 ◽  
Vol 312 (4) ◽  
pp. F744-F747 ◽  
Author(s):  
Emma T. B. Olesen ◽  
Robert A. Fenton
Keyword(s):  
Collecting Duct ◽  
Water Channel ◽  
Cyclic Adenosine Monophosphate ◽  
Adenosine Monophosphate ◽  
Peptide Hormone ◽  
Apical Plasma Membrane ◽  
Crucial Importance ◽  
Aquaporin 2

The targeting of the water channel aquaporin-2 (AQP2) to the apical plasma membrane of kidney collecting duct principal cells is regulated mainly by the antidiuretic peptide hormone arginine vasopressin (AVP). This process is of crucial importance for the maintenance of body water homeostasis. In this brief review we assess the role of cyclic adenosine monophosphate (cAMP) and discuss the emerging concept that type 2 AVP receptor (V2R)-mediated AQP2 trafficking is cAMP-independent.

NMR and EPR studies of membrane transporters

2009 ◽  
Vol 390 (8) ◽  
Author(s):  
Ute A. Hellmich ◽  
Clemens Glaubitz
Keyword(s):  
Membrane Proteins ◽  
Conformational Changes ◽  
Protein Interactions ◽  
Conformational Dynamics ◽  
Crystallographic Analysis ◽  
Membrane Transporters ◽  
Paramagnetic Resonance ◽  
Substrate Protein ◽  
Electron Paramagnetic

AbstractIn order to fulfill their function, membrane transport proteins have to cycle through a number of conformational and/or energetic states. Thus, understanding the role of conformational dynamics seems to be the key for elucidation of the functional mechanism of these proteins. However, membrane proteins in general are often difficult to express heterologously and in sufficient amounts for structural studies. It is especially challenging to trap a stable energy minimum, e.g., for crystallographic analysis. Furthermore, crystallization is often only possible by subjecting the protein to conditions that do not resemble its native environment and crystals can only be snapshots of selected conformational states. Nuclear magnetic resonance (NMR) and electron paramagnetic resonance (EPR) spectroscopy are complementary methods that offer unique possibilities for studying membrane proteins in their natural membrane environment and for investigating functional conformational changes, lipid interactions, substrate-lipid and substrate-protein interactions, oligomerization states and overall dynamics of membrane transporters. Here, we review recent progress in the field including studies from primary and secondary active transporters.

scholarly journals Role of Deubiquitinases in Human Cancers: Potential Targeted Therapy

2020 ◽  
Vol 21 (7) ◽  
pp. 2548 ◽  
Author(s):  
Keng Po Lai ◽  
Jian Chen ◽  
William Ka Fai Tse
Keyword(s):  
Posttranslational Modifications ◽  
Cancer Biology ◽  
Cell Cycle Control ◽  
Basic Knowledge ◽  
Cellular Functions ◽  
Human Cancers ◽  
Downstream Effectors ◽  
Damage Response ◽  
The Relationship

Deubiquitinases (DUBs) are involved in various cellular functions. They deconjugate ubiquitin (UBQ) from ubiquitylated substrates to regulate their activity and stability. Studies on the roles of deubiquitylation have been conducted in various cancers to identify the carcinogenic roles of DUBs. In this review, we evaluate the biological roles of DUBs in cancer, including proliferation, cell cycle control, apoptosis, the DNA damage response, tumor suppression, oncogenesis, and metastasis. This review mainly focuses on the regulation of different downstream effectors and pathways via biochemical regulation and posttranslational modifications. We summarize the relationship between DUBs and human cancers and discuss the potential of DUBs as therapeutic targets for cancer treatment. This review also provides basic knowledge of DUBs in the development of cancers and highlights the importance of DUBs in cancer biology.

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