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AAA+ ATPase

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https://www.readbyqxmd.com/read/29153394/vcp-p97-mediated-unfolding-as-a-principle-in-protein-homeostasis-and-signaling
#1
REVIEW
Johannes van den Boom, Hemmo Meyer
The AAA+-type ATPase p97 governs an ever-expanding number of cellular processes reaching from degradation of damaged proteins and organelles to key signaling events and chromatin regulation with thousands of client proteins. With its relevance for cellular homeostasis and genome stability, it is linked to muscular and neuronal degeneration and, conversely, constitutes an attractive anti-cancer drug target. Its molecular function is ATP-driven protein unfolding, which is directed by ubiquitin and assisted by a host of cofactor proteins...
November 15, 2017: Molecular Cell
https://www.readbyqxmd.com/read/29138251/mitochondrial-inner-membrane-protease-yme1-degrades-outer-membrane-proteins-tom22-and-om45
#2
Xi Wu, Lanlan Li, Hui Jiang
Mitochondria are double-membraned organelles playing essential metabolic and signaling functions. The mitochondrial proteome is under surveillance by two proteolysis systems: the ubiquitin-proteasome system degrades mitochondrial outer-membrane (MOM) proteins, and the AAA proteases maintain the proteostasis of intramitochondrial compartments. We previously identified a Doa1-Cdc48(-Ufd1-Npl4) complex that retrogradely translocates ubiquitinated MOM proteins to the cytoplasm for degradation. In this study, we report the unexpected identification of MOM proteins whose degradation requires the Yme1(-Mgr1-Mgr3)i-AAA protease complex in mitochondrial inner membrane...
November 14, 2017: Journal of Cell Biology
https://www.readbyqxmd.com/read/29113992/axonemal-dynein-assembly-requires-the-r2tp-complex-component-pontin
#3
Yuanyuan Li, Lu Zhao, Shiaulou Yuan, Jiefang Zhang, Zhaoxia Sun
Pontin (Ruvbl1) and Reptin (Ruvbl2) are closely related AAA ATPases. They are components of the Ruvbl1-Rvubl2-Tah1-Pih1 (R2TP) complexes that function as co-chaperones for the assembly of multiple macromolecular protein complexes. Here, we show that Pontin is essential for cilia motility in both zebrafish and mouse and that Pontin and Reptin function cooperatively in this process. pontin zebrafish mutants display phenotypes tightly associated with cilia defects and cilia motility is lost in a number of ciliated tissues along with a reduction in the number of both outer and inner dynein arms (ODAs and IDAs)...
November 7, 2017: Development
https://www.readbyqxmd.com/read/29107693/wdr74-participates-in-an-early-cleavage-of-the-pre-rrna-processing-pathway-in-cooperation-with-the-nucleolar-aaa-atpase-nvl2
#4
Nobuhiro Hiraishi, Yo-Ichi Ishida, Haruka Sudo, Masami Nagahama
WD repeat-containing protein 74 (WDR74), a nucleolar-localized protein, is the mammalian ortholog of Nsa1, a 60S ribosome assembly factor in yeast. We previously showed that WDR74 associates with MTR4, the nuclear exosome-assisting RNA helicase, whose dissociation is prohibited by an ATPase-deficient mutant of the AAA-type chaperone NVL2. However, the functions and regulation of WDR74 during ribosome biogenesis in cooperation with NVL2 remains unknown. Here, we demonstrated that knockdown of WDR74 leads to significant defects in the pre-rRNA cleavage within the internal transcribed spacer 1 (ITS1), occurring in an early stage of the processing pathway...
October 28, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/29103092/stress-induced-oryza-sativa-ruvbl1a-is-dna-independent-atpase-and-unwinds-dna-duplex-in-3-to-5-direction
#5
Shabnam K Saifi, Nishat Passricha, Renu Tuteja, Narendra Tuteja
RuvB, a member of AAA+ (ATPases Associated with diverse cellular Activities) superfamily of proteins, is essential, highly conserved and multifunctional in nature as it is involved in DNA damage repair, mitotic assembly, switching of histone variants and assembly of telomerase core complex. RuvB family is widely studied in various systems such as Escherichia coli, yeast, human, Drosophila, Plasmodium falciparum and mouse, but not well studied in plants. We have studied the transcript level of rice homologue of RuvB gene (OsRuvBL1a) under various abiotic stress conditions, and the results suggest that it is upregulated under salinity, cold and heat stress...
November 4, 2017: Protoplasma
https://www.readbyqxmd.com/read/29097679/structural-basis-of-katanin-p60-p80-complex-formation
#6
Lenka Rezabkova, Kai Jiang, Guido Capitani, Andrea E Prota, Anna Akhmanova, Michel O Steinmetz, Richard A Kammerer
Interactions between microtubule (MT) interacting and trafficking (MIT) domains and their binding proteins are important for the accurate progression of many cellular processes that require the AAA+ ATPase machinery. Therefore, knowledge on the structural basis of MIT domain interactions is crucial for understanding the molecular mechanisms underlying AAA+ ATPase function. Katanin is a MT-severing AAA+ ATPase that consists of p60 and p80 subunits. Although, the hexameric p60 subunit is active alone, its association with the p80 subunit greatly enhances both the MT-binding and -severing activities of katanin...
November 2, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29097521/structure-of-the-mitochondrial-inner-membrane-aaa-protease-yme1-gives-insight-into-substrate-processing
#7
Cristina Puchades, Anthony J Rampello, Mia Shin, Christopher J Giuliano, R Luke Wiseman, Steven E Glynn, Gabriel C Lander
We present an atomic model of a substrate-bound inner mitochondrial membrane AAA+ quality control protease in yeast, YME1. Our ~3.4-angstrom cryo-electron microscopy structure reveals how the adenosine triphosphatases (ATPases) form a closed spiral staircase encircling an unfolded substrate, directing it toward the flat, symmetric protease ring. Three coexisting nucleotide states allosterically induce distinct positioning of tyrosines in the central channel, resulting in substrate engagement and translocation to the negatively charged proteolytic chamber...
November 3, 2017: Science
https://www.readbyqxmd.com/read/29074727/liver-reptin-ruvbl2-controls-glucose-and-lipid-metabolism-with-opposite-actions-on-mtorc1-and-mtorc2-signalling
#8
Joaquim Javary, Nathalie Allain-Courtois, Nicolas Saucisse, Pierre Costet, Capucine Heraud, Fadila Benhamed, Rémi Pierre, Corinne Bure, Nestor Pallares-Lupon, Marcio Do Cruzeiro, Catherine Postic, Daniela Cota, Pierre Dubus, Jean Rosenbaum, Samira Benhamouche-Trouillet
OBJECTIVE: The AAA+ ATPase Reptin is overexpressed in hepatocellular carcinoma and preclinical studies indicate that it could be a relevant therapeutic target. However, its physiological and pathophysiological roles in vivo remain unknown. This study aimed to determine the role of Reptin in mammalian adult liver. DESIGN AND RESULTS: We generated an inducible liver-specific Reptin knockout (Repin(LKO) ) mouse model. Following Reptin invalidation, mice displayed decreased body and fat mass, hypoglycaemia and hypolipidaemia...
October 26, 2017: Gut
https://www.readbyqxmd.com/read/29030426/molecular-insights-into-the-m-aaa-protease-mediated-dislocation-of-transmembrane-helices-in-the-mitochondrial-inner-membrane
#9
Seoeun Lee, Hunsang Lee, Suji Yoo, Hyun Kim
In the mitochondrial inner membrane, many protein complexes involved in respiration, ATP synthesis, and protein import reside, thus proper regulation of these proteins is essential for cell viability. The mAAA protease, a conserved heterohexameric AAA (ATPases associated with diverse cellular activities) protease composed of the Yta10 and Yta12 proteins, regulates mitochondrial proteostasis by mediating protein maturation and degradation. It also recognizes and mediates dislocation of membrane embedded substrates, including foreign transmembrane (TM) segments, yet the molecular mechanism involved in these processes remains elusive...
October 13, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29021797/the-rice-aaa-atpase-osfignl1-is-essential-for-male-meiosis
#10
Peipei Zhang, Yingxin Zhang, Lianping Sun, Sittipun Sinumporn, Zhengfu Yang, Bin Sun, Dandan Xuan, Zihe Li, Ping Yu, Weixun Wu, Kejian Wang, Liyong Cao, Shihua Cheng
Meiosis is crucial in reproduction of plants and ensuring genetic diversity. Although several genes involved in homologous recombination and DNA repair have been reported, their functions in rice (Oryza sativa) male meiosis remain poorly understood. Here, we isolated and characterized the rice OsFIGNL1 (OsFidgetin-like 1) gene, encoding a conserved AAA-ATPase, and explored its function and importance in male meiosis and pollen formation. The rice Osfignl1 mutant exhibited normal vegetative growth, but failed to produce seeds and displayed pollen abortion phenotype...
2017: Frontiers in Plant Science
https://www.readbyqxmd.com/read/28949448/vcp-inhibitors-induce-endoplasmic-reticulum-stress-cause%C3%A2-cell-cycle-arrest-trigger-caspase-mediated-cell-death%C3%A2-and-synergistically-kill-ovarian-cancer-cells-in-combination-with-salubrinal
#11
(no author information available yet)
Valosin-containing protein (VCP) or p97, a member of AAA-ATPase protein family, has been associated with various cellular functions including endoplasmic reticulum-associated degradation (ERAD), Golgi membrane reassembly, autophagy, DNA repair, and cell division. Recent studies identified VCP and ubiquitin proteasome system (UPS) as synthetic lethal targets in ovarian cancer. Here, we describe the preclinical activity of VCP inhibitors in ovarian cancer. Results from our studies suggest that quinazoline-based VCP inhibitors initiate G1 cell cycle arrest, attenuate cap-dependent translation and induce programmed cell death via the intrinsic and the extrinsic modes of apoptosis...
December 2016: Molecular Oncology
https://www.readbyqxmd.com/read/28941010/atad3-proteins-brokers-of-a-mitochondria-endoplasmic-reticulum-connection-in-mammalian-cells
#12
Jacques Baudier
In yeast, a sequence of physical and genetic interactions termed the endoplasmic reticulum (ER)-mitochondria organizing network (ERMIONE) controls mitochondria-ER interactions and mitochondrial biogenesis. Several functions that characterize ERMIONE complexes are conserved in mammalian cells, suggesting that a similar tethering complex must exist in metazoans. Recent studies have identified a new family of nuclear-encoded ATPases associated with diverse cellular activities (AAA+-ATPase) mitochondrial membrane proteins specific to multicellular eukaryotes, called the ATPase family AAA domain-containing protein 3 (ATAD3) proteins (ATAD3A and ATAD3B)...
September 20, 2017: Biological Reviews of the Cambridge Philosophical Society
https://www.readbyqxmd.com/read/28939772/interaction-between-the-aaa-atpase-p97-and-its-cofactor-ataxin3-in-health-and-disease-nucleotide-induced-conformational-changes-regulate-cofactor-binding
#13
Maya V Rao, Dewight R Williams, Simon Cocklin, Patrick J Loll
p97 is an essential ATPase associated with various cellular activities (AAA(+)) that functions as a segregase in diverse cellular processes, including the maintenance of proteostasis. p97 interacts with different cofactors that target it to distinct pathways; an important example is the deubiquitinase ataxin3, which collaborates with p97 in endoplasmic reticulum-associated degradation. However, the molecular details of this interaction have been unclear. Here, we characterized the binding of ataxin3 to p97, showing that ataxin3 binds with low-micromolar affinity to both wild-type p97 and mutants linked to degenerative disorders known as multisystem proteinopathy 1 (MSP1); we further showed that the stoichiometry of binding is one ataxin3 molecule per p97 hexamer...
November 10, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28919439/pih1p-tah1p-puts-a-lid-on-hexameric-aaa-atpases-rvb1-2p
#14
Shaoxiong Tian, Ge Yu, Huan He, Yu Zhao, Peilu Liu, Alan G Marshall, Borries Demeler, Scott M Stagg, Hong Li
The Saccharomyces cerevisiae (Sc) R2TP complex affords an Hsp90-mediated and nucleotide-driven chaperone activity to proteins of small ribonucleoprotein particles (snoRNPs). The current lack of structural information on the ScR2TP complex, however, prevents a mechanistic understanding of this biological process. We characterized the structure of the ScR2TP complex made up of two AAA+ ATPases, Rvb1/2p, and two Hsp90 binding proteins, Tah1p and Pih1p, and its interaction with the snoRNP protein Nop58p by a combination of analytical ultracentrifugation, isothermal titration calorimetry, chemical crosslinking, hydrogen-deuterium exchange, and cryoelectron microscopy methods...
August 24, 2017: Structure
https://www.readbyqxmd.com/read/28906250/the-aaa-protein-msp1-mediates-clearance-of-excess-tail-anchored-proteins-from-the-peroxisomal-membrane
#15
Nicholas R Weir, Roarke A Kamber, James S Martenson, Vladimir Denic
Msp1 is a conserved AAA ATPase in budding yeast localized to mitochondria where it prevents accumulation of mistargeted tail-anchored (TA) proteins, including the peroxisomal TA protein Pex15. Msp1 also resides on peroxisomes but it remains unknown how native TA proteins on mitochondria and peroxisomes evade Msp1 surveillance. We used live-cell quantitative cell microscopy tools and drug-inducible gene expression to dissect Msp1 function. We found that a small fraction of peroxisomal Pex15, exaggerated by overexpression, is turned over by Msp1...
September 14, 2017: ELife
https://www.readbyqxmd.com/read/28903051/features-of-the-chaperone-cellular-network-revealed-through-systematic-interaction-mapping
#16
Kamran Rizzolo, Jennifer Huen, Ashwani Kumar, Sadhna Phanse, James Vlasblom, Yoshito Kakihara, Hussein A Zeineddine, Zoran Minic, Jamie Snider, Wen Wang, Carles Pons, Thiago V Seraphim, Edgar Erik Boczek, Simon Alberti, Michael Costanzo, Chad L Myers, Igor Stagljar, Charles Boone, Mohan Babu, Walid A Houry
A comprehensive view of molecular chaperone function in the cell was obtained through a systematic global integrative network approach based on physical (protein-protein) and genetic (gene-gene or epistatic) interaction mapping. This allowed us to decipher interactions involving all core chaperones (67) and cochaperones (15) of Saccharomyces cerevisiae. Our analysis revealed the presence of a large chaperone functional supercomplex, which we named the naturally joined (NAJ) chaperone complex, encompassing Hsp40, Hsp70, Hsp90, AAA+, CCT, and small Hsps...
September 12, 2017: Cell Reports
https://www.readbyqxmd.com/read/28892477/allosteric-conformational-change-cascade-in-cytoplasmic-dynein-revealed-by-structure-based-molecular-simulations
#17
Shintaroh Kubo, Wenfei Li, Shoji Takada
Cytoplasmic dynein is a giant ATP-driven molecular motor that proceeds to the minus end of the microtubule (MT). Dynein hydrolyzes ATP in a ring-like structure, containing 6 AAA+ (ATPases associated with diverse cellular activities) modules, which is ~15 nm away from the MT binding domain (MTBD). This architecture implies that long-distance allosteric couplings exist between the AAA+ ring and the MTBD in order for dynein to move on the MT, although little is known about the mechanisms involved. Here, we have performed comprehensive molecular simulations of the dynein motor domain based on pre- and post- power-stroke structural information and in doing so we address the allosteric conformational changes that occur during the power-stroke and recovery-stroke processes...
September 2017: PLoS Computational Biology
https://www.readbyqxmd.com/read/28884116/the-role-of-pontin-and-reptin-in-cellular-physiology-and-cancer-etiology
#18
REVIEW
Yu-Qian Mao, Walid A Houry
Pontin (RUVBL1, TIP49, TIP49a, Rvb1) and Reptin (RUVBL2, TIP48, TIP49b, Rvb2) are highly conserved ATPases of the AAA+ (ATPases Associated with various cellular Activities) superfamily and are involved in various cellular processes that are important for oncogenesis. First identified as being upregulated in hepatocellular carcinoma and colorectal cancer, their overexpression has since been shown in multiple cancer types such as breast, lung, gastric, esophageal, pancreatic, kidney, bladder as well as lymphatic, and leukemic cancers...
2017: Frontiers in Molecular Biosciences
https://www.readbyqxmd.com/read/28879184/hsp78-78-kda-heat-shock-protein-a-representative-aaa-family-member-found-in-the-mitochondrial-matrix-of-saccharomyces-cerevisiae
#19
REVIEW
Josielle Abrahão, David Z Mokry, Carlos H I Ramos
ATPases associated with diverse cellular activities (AAA+) form a superfamily of proteins involved in a variety of functions and are characterized by the presence of an ATPase module containing two conserved motifs known as Walker A and Walker B. ClpB and Hsp104, chaperones that have disaggregase activities, are members of a subset of this superfamily, known as the AAA family, and are characterized by the presence of a second highly conserved motif, known as the second region of homology (SRH). Hsp104 and its homolog Hsp78 (78 kDa heat shock protein) are representatives of the Clp family in yeast...
2017: Frontiers in Molecular Biosciences
https://www.readbyqxmd.com/read/28878026/the-p97-inhibitor-cb-5083-is-a-unique-disrupter-of-protein-homeostasis-in-models-of-multiple-myeloma
#20
Ronan Le Moigne, Blake T Aftab, Stevan Djakovic, Eugen Dhimolea, Eduardo Valle, Megan Murnane, Emily M King, Ferdie Soriano, Mary-Kamala Menon, Zhi Yong Wu, Stephen T Wong, Grace J Lee, Bing Yao, Arun P Wiita, Christine Lam, Julie Rice, Jinhai Wang, Marta Chesi, P Leif Bergsagel, Marianne Kraus, Christoph Driessen, Szerenke Kiss von Soly, F Michael Yakes, David Wustrow, Laura Shawver, Han-Jie Zhou, Thomas G Martin, Jeffrey L Wolf, Constantine S Mitsiades, Daniel J Anderson, Mark Rolfe
Inhibition of the AAA ATPase, p97, was recently shown to be a novel method for targeting the ubiquitin proteasome system, and CB-5083, a first-in-class inhibitor of p97, has demonstrated broad antitumor activity in a range of both hematologic and solid tumor models. Here, we show that CB-5083 has robust activity against multiple myeloma cell lines and a number of in vivo multiple myeloma models. Treatment with CB-5083 is associated with accumulation of ubiquitinated proteins, induction of the unfolded protein response, and apoptosis...
November 2017: Molecular Cancer Therapeutics
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