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Biochemical Society Transactions Oct 2015The ATP-binding cassette (ABC) transporters are primary transporters that couple the energy stored in adenosine triphosphate (ATP) to the movement of molecules across... (Review)
Review
The ATP-binding cassette (ABC) transporters are primary transporters that couple the energy stored in adenosine triphosphate (ATP) to the movement of molecules across the membrane. ABC transporters can be divided into exporters and importers; importers mediate the uptake of essential nutrients into cells and are found predominantly in prokaryotes whereas exporters transport molecules out of cells or into organelles and are found in all organisms. ABC exporters have been linked with multi-drug resistance in both bacterial and eukaryotic cells. ABC transporters are powered by the hydrolysis of ATP and transport their substrate via the alternating access mechanism, whereby the protein alternates between a conformation in which the substrate-binding site is accessible from the outside of the membrane, outward-facing and one in which it is inward-facing. In this mini-review, the structures of different ABC transporter types in different conformations are presented within the context of the alternating access mechanism and how they have shaped our current understanding of the mechanism of ABC transporters.
Topics: ATP-Binding Cassette Transporters; Adenosine Triphosphatases; Animals; Biocatalysis; Biological Transport, Active; Drug Resistance, Multiple; Humans; Isoenzymes; Models, Molecular; Mutation; Protein Conformation; Protein Isoforms; Protein Structure, Tertiary
PubMed: 26517899
DOI: 10.1042/BST20150047 -
Trends in Molecular Medicine Nov 2022Moyamoya disease (MMD) is a rare cerebrovascular disorder with unknown etiology. MMD is characterized by progressive narrowing of arteries of the brain and the formation... (Review)
Review
Moyamoya disease (MMD) is a rare cerebrovascular disorder with unknown etiology. MMD is characterized by progressive narrowing of arteries of the brain and the formation of a compensatory network of fragile vessels. Genetic studies have identified RNF213, also known as mysterin, as a susceptibility gene for MMD, but the low penetrance in genetically susceptible individuals suggests that a second hit is necessary to trigger disease onset. Recently, several molecular studies uncovered RNF213 as a key antimicrobial protein with important functions in the immune system. In addition, an increasing number of clinical reports describe the development of moyamoya angiopathy (MMA) associated with infection or autoimmune disorders. Together, this growing body of molecular and clinical evidence points towards immune-related responses as second hits to trigger MMD onset.
Topics: Humans; Moyamoya Disease; Adenosine Triphosphatases; Ubiquitin-Protein Ligases; Genetic Predisposition to Disease; Transcription Factors
PubMed: 36115805
DOI: 10.1016/j.molmed.2022.08.009 -
Science (New York, N.Y.) Jun 2014Phospholipids are asymmetrically distributed in the plasma membrane. This asymmetrical distribution is disrupted during apoptosis, exposing phosphatidylserine (PtdSer)...
Phospholipids are asymmetrically distributed in the plasma membrane. This asymmetrical distribution is disrupted during apoptosis, exposing phosphatidylserine (PtdSer) on the cell surface. Using a haploid genetic screen in human cells, we found that ATP11C (adenosine triphosphatase type 11C) and CDC50A (cell division cycle protein 50A) are required for aminophospholipid translocation from the outer to the inner plasma membrane leaflet; that is, they display flippase activity. ATP11C contained caspase recognition sites, and mutations at these sites generated caspase-resistant ATP11C without affecting its flippase activity. Cells expressing caspase-resistant ATP11C did not expose PtdSer during apoptosis and were not engulfed by macrophages, which suggests that inactivation of the flippase activity is required for apoptotic PtdSer exposure. CDC50A-deficient cells displayed PtdSer on their surface and were engulfed by macrophages, indicating that PtdSer is sufficient as an "eat me" signal.
Topics: Adenosine Triphosphatases; Apoptosis; Caspases; Cell Line; Cell Membrane; Genetic Testing; Humans; Membrane Proteins; Membrane Transport Proteins; Phosphatidylserines; Phospholipid Transfer Proteins; Protein Transport
PubMed: 24904167
DOI: 10.1126/science.1252809 -
Nature May 2019Chromatin remodelling complexes evict, slide, insert or replace nucleosomes, which represent an intrinsic barrier for access to DNA. These remodellers function in most...
Chromatin remodelling complexes evict, slide, insert or replace nucleosomes, which represent an intrinsic barrier for access to DNA. These remodellers function in most aspects of genome utilization including transcription-factor binding, DNA replication and repair. Although they are frequently mutated in cancer, it remains largely unclear how the four mammalian remodeller families (SWI/SNF, ISWI, CHD and INO80) orchestrate the global organization of nucleosomes. Here we generated viable embryonic stem cells that lack SNF2H, the ATPase of ISWI complexes, enabling study of SNF2H cellular function, and contrast it to BRG1, the ATPase of SWI/SNF. Loss of SNF2H decreases nucleosomal phasing and increases linker lengths, providing in vivo evidence for an ISWI function in ruling nucleosomal spacing in mammals. Systematic analysis of transcription-factor binding reveals that these remodelling activities have specific effects on binding of different transcription factors. One group critically depends on BRG1 and contains the transcriptional repressor REST, whereas a non-overlapping set of transcription factors, including the insulator protein CTCF, relies on SNF2H. This selectivity readily explains why chromosomal folding and insulation of topologically associated domains requires SNF2H, but not BRG1. Collectively, this study shows that mammalian ISWI is critical for nucleosomal periodicity and nuclear organization and that transcription factors rely on specific remodelling pathways for correct genomic binding.
Topics: Adenosine Triphosphatases; Animals; Chromosomal Proteins, Non-Histone; DNA Helicases; DNA-Binding Proteins; Embryonic Stem Cells; Mice; Nuclear Proteins; Nucleosomes; Protein Binding; Transcription Factors
PubMed: 30996347
DOI: 10.1038/s41586-019-1115-5 -
Journal of Immunology (Baltimore, Md. :... May 2021Nucleoside triphosphate diphosphohydrolases (NTPDases) are a family of enzymes that hydrolyze nucleotides such as ATP, UTP, ADP, and UDP to monophosphates derivates such... (Review)
Review
Nucleoside triphosphate diphosphohydrolases (NTPDases) are a family of enzymes that hydrolyze nucleotides such as ATP, UTP, ADP, and UDP to monophosphates derivates such as AMP and UMP. The NTPDase family consists of eight enzymes, of which NTPDases 1, 2, 3, and 8 are expressed on cell membranes thereby hydrolyzing extracellular nucleotides. Cell membrane NTPDases are expressed in all tissues, in which they regulate essential physiological tissue functions such as development, blood flow, hormone secretion, and neurotransmitter release. They do so by modulating nucleotide-mediated purinergic signaling through P2 purinergic receptors. NTPDases 1, 2, 3, and 8 also play a key role during infection, inflammation, injury, and cancer. Under these conditions, NTPDases can contribute and control the pathophysiology of infectious, inflammatory diseases and cancer. In this review, we discuss the role of NTPDases, focusing on the less understood NTPDases 2-8, in regulating inflammation and immunity during infectious, inflammatory diseases, and cancer.
Topics: Adenosine Triphosphatases; Animals; Gene Expression Regulation, Enzymologic; Humans; Immunity; Inflammation; Isoenzymes; Multigene Family; Neoplasms; Nucleotides
PubMed: 33879578
DOI: 10.4049/jimmunol.2001342 -
Critical Reviews in Biochemistry and... 2016Cellular membranes display a diversity of functions that are conferred by the unique composition and organization of their proteins and lipids. One important aspect of... (Review)
Review
Cellular membranes display a diversity of functions that are conferred by the unique composition and organization of their proteins and lipids. One important aspect of lipid organization is the asymmetric distribution of phospholipids (PLs) across the plasma membrane. The unequal distribution of key PLs between the cytofacial and exofacial leaflets of the bilayer creates physical surface tension that can be used to bend the membrane; and like Ca, a chemical gradient that can be used to transduce biochemical signals. PL flippases in the type IV P-type ATPase (P4-ATPase) family are the principle transporters used to set and repair this PL gradient and the asymmetric organization of these membranes are encoded by the substrate specificity of these enzymes. Thus, understanding the mechanisms of P4-ATPase substrate specificity will help reveal their role in membrane organization and cell biology. Further, decoding the structural determinants of substrate specificity provides investigators the opportunity to mutationally tune this specificity to explore the role of particular PL substrates in P4-ATPase cellular functions. This work reviews the role of P4-ATPases in membrane biology, presents our current understanding of P4-ATPase substrate specificity, and discusses how these fundamental aspects of P4-ATPase enzymology may be used to enhance our knowledge of cellular membrane biology.
Topics: Adenosine Triphosphatases; Animals; Cell Membrane; Humans; Models, Molecular; Phospholipid Transfer Proteins; Phospholipids; Protein Domains; Substrate Specificity
PubMed: 27696908
DOI: 10.1080/10409238.2016.1237934 -
Biochimica Et Biophysica Acta.... Oct 2023Calcium (Ca)-ATPases are ATP-dependent enzymes that transport Ca ions against their electrochemical gradient playing the fundamental biological function of keeping the... (Review)
Review
Calcium (Ca)-ATPases are ATP-dependent enzymes that transport Ca ions against their electrochemical gradient playing the fundamental biological function of keeping the free cytosolic Ca concentration in the submicromolar range to prevent cytotoxic effects. In plants, type IIB autoinhibited Ca-ATPases (ACAs) are localised both at the plasma membrane and at the endomembranes including endoplasmic reticulum (ER) and tonoplast and their activity is primarily regulated by Ca-dependent mechanisms. Instead, type IIA ER-type Ca-ATPases (ECAs) are present mainly at the ER and Golgi Apparatus membranes and are active at resting Ca. Whereas research in plants has historically focused on the biochemical characterization of these pumps, more recently the attention has been also addressed on the physiological roles played by the different isoforms. This review aims to highlight the main biochemical properties of both type IIB and type IIA Ca pumps and their involvement in the shaping of cellular Ca dynamics induced by different stimuli.
Topics: Adenosine Triphosphatases; Calcium-Transporting ATPases; Plants; Signal Transduction; Cell Membrane
PubMed: 37290725
DOI: 10.1016/j.bbamcr.2023.119508 -
Biochimica Et Biophysica Acta Aug 2014The Type III Secretion System (T3SS) is a multi-mega Dalton apparatus assembled from more than twenty components and is found in many species of animal and plant... (Review)
Review
The Type III Secretion System (T3SS) is a multi-mega Dalton apparatus assembled from more than twenty components and is found in many species of animal and plant bacterial pathogens. The T3SS creates a contiguous channel through the bacterial and host membranes, allowing injection of specialized bacterial effector proteins directly to the host cell. In this review, we discuss our current understanding of T3SS assembly and structure, as well as highlight structurally characterized Salmonella effectors. This article is part of a Special Issue entitled: Protein trafficking and secretion in bacteria. Guest Editors: Anastassios Economou and Ross Dalbey.
Topics: Adenosine Triphosphatases; Bacterial Secretion Systems; Gram-Negative Bacteria; Membrane Proteins; Molecular Chaperones; Multiprotein Complexes; Protein Structure, Tertiary; Protein Transport
PubMed: 24512838
DOI: 10.1016/j.bbamcr.2014.01.035 -
Nature Communications Jul 2023Cellular homeostasis is governed by removal of damaged organelles and protein aggregates by selective autophagy mediated by cargo adaptors such as p62/SQSTM1....
Cellular homeostasis is governed by removal of damaged organelles and protein aggregates by selective autophagy mediated by cargo adaptors such as p62/SQSTM1. Autophagosomes can assemble in specialized cup-shaped regions of the endoplasmic reticulum (ER) known as omegasomes, which are characterized by the presence of the ER protein DFCP1/ZFYVE1. The function of DFCP1 is unknown, as are the mechanisms of omegasome formation and constriction. Here, we demonstrate that DFCP1 is an ATPase that is activated by membrane binding and dimerizes in an ATP-dependent fashion. Whereas depletion of DFCP1 has a minor effect on bulk autophagic flux, DFCP1 is required to maintain the autophagic flux of p62 under both fed and starved conditions, and this is dependent on its ability to bind and hydrolyse ATP. While DFCP1 mutants defective in ATP binding or hydrolysis localize to forming omegasomes, these omegasomes fail to constrict properly in a size-dependent manner. Consequently, the release of nascent autophagosomes from large omegasomes is markedly delayed. While knockout of DFCP1 does not affect bulk autophagy, it inhibits selective autophagy, including aggrephagy, mitophagy and micronucleophagy. We conclude that DFCP1 mediates ATPase-driven constriction of large omegasomes to release autophagosomes for selective autophagy.
Topics: Macroautophagy; Autophagy; Endoplasmic Reticulum; Adenosine Triphosphatases; Adenosine Triphosphate
PubMed: 37422481
DOI: 10.1038/s41467-023-39641-9 -
Cellular and Molecular Life Sciences :... Mar 2017ATPases Associated with various cellular Activities (AAA+ ATPases) are molecular motors that use the energy of ATP binding and hydrolysis to remodel their target... (Review)
Review
ATPases Associated with various cellular Activities (AAA+ ATPases) are molecular motors that use the energy of ATP binding and hydrolysis to remodel their target macromolecules. The majority of these ATPases form ring-shaped hexamers in which the active sites are located at the interfaces between neighboring subunits. Structural changes initiate in an active site and propagate to distant motor parts that interface and reshape the target macromolecules, thereby performing mechanical work. During the functioning cycle, the AAA+ motor transits through multiple distinct states. Ring architecture and placement of the catalytic sites at the intersubunit interfaces allow for a unique level of coordination among subunits of the motor. This in turn results in conformational differences among subunits and overall asymmetry of the motor ring as it functions. To date, a large amount of structural information has been gathered for different AAA+ motors, but even for the most characterized of them only a few structural states are known and the full mechanistic cycle cannot be yet reconstructed. Therefore, the first part of this work will provide a broad overview of what arrangements of AAA+ subunits have been structurally observed focusing on diversity of ATPase oligomeric ensembles and heterogeneity within the ensembles. The second part of this review will concentrate on methods that assess structural and functional heterogeneity among subunits of AAA+ motors, thus bringing us closer to understanding the mechanism of these fascinating molecular motors.
Topics: Adenosine Triphosphatases; Adenosine Triphosphate; Amino Acid Sequence; Animals; Humans; Hydrolysis; Models, Molecular; Protein Multimerization; Protein Subunits
PubMed: 27669691
DOI: 10.1007/s00018-016-2374-z