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https://www.readbyqxmd.com/read/29142102/prolines-in-the-%C3%AE-helix-confer-the-structural-flexibility-and-functional-integrity-of-importin-%C3%AE
#1
Masahiro Kumeta, Hide A Konishi, Wanzhen Zhang, Sayuri Sakagami, Shige H Yoshimura
The karyopherin family of nuclear transport receptors is composed of a long array of amphiphilic α-helices and undergoes flexible conformational changes to pass through the hydrophobic crowding barrier of the nuclear pore. Here, we focused on the characteristic enrichment of prolines in the middle of the outer α-helices of importin β. When these prolines were substituted with alanine, nuclear transport activity was reduced drastically in vivo and in vitro, and caused a severe defect in mitotic progression...
November 15, 2017: Journal of Cell Science
https://www.readbyqxmd.com/read/29127199/the-full-length-interleukin-33-flil33-importin-5-interaction-does-not-regulate-flil33-s-nuclear-localization-but-controls-its-intracellular-degradation
#2
Andrew Clerman, Zahid Noor, Rita Fishelevich, Virginia Lockatell, Brian S Hampton, Nirav G Shah, Mariah V Salcedo, Nevins W Todd, Sergei P Atamas, Irina G Luzina
Human mature interleukin-33 (MIL33) is a member of the IL-1 family and a potent regulator of immunity through its pro-T helper cell 2 (Th2) activity. Its precursor form, full-length interleukin-33 (FLIL33), is an intranuclear protein in many cell types, including fibroblasts, and its intracellular levels can change in response to stimuli. However, the mechanisms controlling the nuclear localization of FLIL33 or its stability in cells are not understood. Here, we identified importin-5 (IPO5), a member of the importin family of nuclear transport proteins, as an intracellular binding partner of FLIL33...
November 10, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29120325/structural-insight-into-tpx2-stimulated-microtubule-assembly
#3
Rui Zhang, Johanna Roostalu, Thomas Surrey, Eva Nogales
During mitosis and meiosis, microtubule (MT) assembly is locally upregulated by the chromatin-dependent Ran-GTP pathway. One of its key targets is the MT-associated spindle assembly factor TPX2. The molecular mechanism of how TPX2 stimulates MT assembly remains unknown because structural information about the interaction of TPX2 with MTs is lacking. Here, we determine the cryo-electron microscopy structure of a central region of TPX2 bound to the MT surface. TPX2 uses two flexibly linked elements ('ridge' and 'wedge') in a novel interaction mode to simultaneously bind across longitudinal and lateral tubulin interfaces...
November 9, 2017: ELife
https://www.readbyqxmd.com/read/29098725/the-structure-of-the-large-regulatory-%C3%AE-subunit-of-phosphorylase-kinase-examined-by-modeling-and-hydrogen-deuterium-exchange
#4
Mary Ashley Rimmer, Owen W Nadeau, Jianyi Yang, Antonio Artigues, Yang Zhang, Gerald M Carlson
Phosphorylase kinase (PhK), a 1.3 MDa regulatory enzyme complex in the glycogenolysis cascade, has four copies each of four subunits, (αβγδ)4 , and 325 kDa of unique sequence (the mass of an αβγδ protomer). The α, β and δ subunits are regulatory, and contain allosteric activation sites that stimulate the activity of the catalytic γ subunit in response to diverse signaling molecules. Due to its size and complexity, no high resolution structures have been solved for the intact complex or its regulatory α and β subunits...
November 3, 2017: Protein Science: a Publication of the Protein Society
https://www.readbyqxmd.com/read/29054975/nuclear-transport-of-the-neurospora-crassa-nit-2-transcription-factor-is-mediated-by-importin-%C3%AE
#5
Natália E Bernardes, Agnes Alessandra S Takeda, Thiago Revers Dreyer, Fernanda B Cupertino, Stela Virgilio, Nelly Pante, Maria Célia Bertolini, Marcos R M Fontes
The Neurospora crassa NIT-2 transcription factor belongs to the GATA transcription factor family and plays a fundamental role in the regulation of nitrogen metabolism by N. crassa Because NIT-2 acts by accessing DNA inside the nucleus, understanding the nuclear import process of NIT-2 is necessary to characterize its function. Thus, in this study, NIT-2 nuclear transport was investigated using a combination of biochemical, cellular and biophysical methods. A complemented strain that produced a sfGFP-NIT-2 fusion protein was constructed, and nuclear localization assessments were made under conditions that favored protein translocation to the nucleus...
October 20, 2017: Biochemical Journal
https://www.readbyqxmd.com/read/29042532/three-dimensional-context-rather-than-nls-amino-acid-sequence-determines-importin-%C3%AE-subtype-specificity-for-rcc1
#6
Rajeshwer S Sankhala, Ravi K Lokareddy, Salma Begum, Ruth A Pumroy, Richard E Gillilan, Gino Cingolani
Active nuclear import of Ran exchange factor RCC1 is mediated by importin α3. This pathway is essential to generate a gradient of RanGTP on chromatin that directs nucleocytoplasmic transport, mitotic spindle assembly and nuclear envelope formation. Here we identify the mechanisms of importin α3 selectivity for RCC1. We find this isoform binds RCC1 with one order of magnitude higher affinity than the generic importin α1, although the two isoforms share an identical NLS-binding groove. Importin α3 uses its greater conformational flexibility to wedge the RCC1 β-propeller flanking the NLS against its lateral surface, preventing steric clashes with its Armadillo-core...
October 17, 2017: Nature Communications
https://www.readbyqxmd.com/read/29017749/characterization-of-the-nuclear-import-pathway-for-blm-protein
#7
Zhiqiang Duan, Jiafu Zhao, Houqiang Xu, Haixu Xu, Xinqin Ji, Xiang Chen, Jianming Xiong
Numerous studies have shown that nuclear localization of BLM protein, a member of the RecQ helicases, mediated by nuclear localization signal (NLS) is critical for DNA recombination, replication and transcription, but the mechanism by which BLM protein is imported into the nucleus remains unknown. In this study, the nuclear import pathway for BLM was investigated. We found that nuclear import of BLM was inhibited by two dominant-negative mutants of importin β1 and NTF2/E42K, which lacks the ability to bind Ran and RanGDP, respectively, but was not inhibited by the Ran/Q69L, which is deficient in GTP hydrolysis...
October 7, 2017: Archives of Biochemistry and Biophysics
https://www.readbyqxmd.com/read/28993511/cell-cycle-dependent-tumor-engraftment-and-migration-are-enabled-by-aurora-a
#8
Tony L H Chu, Marisa Connell, Lixin Zhou, Zhengcheng He, Jennifer R Won, Seyed M Rahavi, Helen Chen, Pooja Mohan, Oksana Nemirovsky, Abbas Fotovati, Miguel Angel Pujana, Gregor Sd Reid, Torsten O Nielsen, Nelly Pante, Christopher A Maxwell
Cell cycle progression and the acquisition of a migratory phenotype are hallmarks of human carcinoma cells that are perceived as independent processes but may be interconnected by molecular pathways that control microtubule nucleation at centrosomes. Here, cell cycle progression dramatically impacts the engraftment kinetics of 4T1-luciferase2 breast cancer cells in immunocompetent BALB/c or immunocompromised NOD-SCID gamma (NSG) mice. Multi-parameter imaging of wound closure assays was used to track cell cycle progression, cell migration, and associated phenotypes in epithelial cells or carcinoma cells expressing a fluorescence ubiquitin cell cycle indicator...
October 9, 2017: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/28991411/structural-insights-into-the-nuclear-import-of-the-histone-acetyltransferase-mof-by-importin-%C3%AE-1
#9
Weili Zheng, Rui Wang, Xi Liu, Siyu Tian, Benqiang Yao, Ang Chen, Shikai Jin, Yong Li
The histone acetyltransferase MOF (males-absent-on-the-first) acetylates the histone H4, a modification important for many biological processes, including chromatin organization, transcriptional regulation, DNA replication, recombination and repair, as well as autophagy. Depletion of MOF induces serious consequences due to the reduction of histone acetylation, such as nuclear morphological defects and cancer. Despite the critical roles of MOF in the nucleus, the structural or functional mechanisms of the nucleocytoplasmic transport of MOF remain elusive...
October 9, 2017: Traffic
https://www.readbyqxmd.com/read/28988109/nuclear-import-inhibitor-n-4-hydroxyphenyl-retinamide-targets-zika-virus-zikv-nonstructural-protein-5-to-inhibit-zikv-infection
#10
Chunxiao Wang, Sundy N Y Yang, Kate Smith, Jade K Forwood, David A Jans
In the absence of approved therapeutics, Zika virus (ZIKV)'s recent prolific outbreaks in the Americas, together with impacts on unborn fetuses of infected mothers, make it a pressing human health concern worldwide. Although a key player in viral replication in the infected host cell cytoplasm, ZIKV non-structural protein 5 (NS5) appears to contribute integrally to pathogenesis by localising in the host cell nucleus, in similar fashion to NS5 from Dengue virus (DENV). We show here for the first time that ZIKV NS5 is recognized with high nanomolar affinity by the host cell importin α/β1 heterodimer, and that this interaction can be blocked by the novel DENV NS5 targeting inhibitor N-(4-hydroxyphenyl) retinamide (4-HPR)...
December 2, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28982779/initiation-of-dna-replication-requires-actin-dynamics-and-formin-activity
#11
Nikolaos Parisis, Liliana Krasinska, Bethany Harker, Serge Urbach, Michel Rossignol, Alain Camasses, James Dewar, Nathalie Morin, Daniel Fisher
Nuclear actin regulates transcriptional programmes in a manner dependent on its levels and polymerisation state. This dynamics is determined by the balance of nucleocytoplasmic shuttling, formin- and redox-dependent filament polymerisation. Here, using Xenopus egg extracts and human somatic cells, we show that actin dynamics and formins are essential for DNA replication. In proliferating cells, formin inhibition abolishes nuclear transport and initiation of DNA replication, as well as general transcription...
November 2, 2017: EMBO Journal
https://www.readbyqxmd.com/read/28968829/the-ns1-protein-of-respiratory-syncytial-virus-blocks-glucocorticoid-receptor-nuclear-translocation-by-targeting-ipo13-may-account-for-glucocorticoid-insensitive
#12
Jun Xie, Xiaoru Long, Leiqiong Gao, Sisi Chen, Keting Zhao, Wei Li, Na Zhou, Na Zang, Yu Deng, Luo Ren, Lijia Wang, Zhengxiu Luo, Wenwei Tu, Xiaodong Zhao, Zhou Fu, Xiaohong Xie, Enmei Liu
In spite of their powerful anti-inflammatory effect, glucocorticoids have shown no significant clinical benefit in respiratory syncytial virus (RSV)-induced bronchiolitis, the reason for which remains unclear. Upon glucocorticoid binding, the cytoplasmic glucocorticoid receptor (GR) translocates to the nucleus with the help of importin-13 (IPO13). Here, we report that RSV infection reduced GR nuclear translocation in the nasopharyngeal aspirate (NPA) of the RSV-infected infants, lungs of infected mice, and A549 cells, which coincided with decreased IPO13 expression...
September 1, 2017: Journal of Infectious Diseases
https://www.readbyqxmd.com/read/28961161/venezuelan-equine-encephalitis-virus-capsid-the-clever-caper
#13
REVIEW
Lindsay Lundberg, Brian Carey, Kylene Kehn-Hall
Venezuelan equine encephalitis virus (VEEV) is a New World alphavirus that is vectored by mosquitos and cycled in rodents. It can cause disease in equines and humans characterized by a febrile illness that may progress into encephalitis. Like the capsid protein of other viruses, VEEV capsid is an abundant structural protein that binds to the viral RNA and interacts with the membrane-bound glycoproteins. It also has protease activity, allowing cleavage of itself from the growing structural polypeptide during translation...
September 29, 2017: Viruses
https://www.readbyqxmd.com/read/28949047/arabidopsis-phosphatidylinositol-4-phosphate-5-kinase-2-contains-a-functional-nuclear-localization-sequence-and-interacts-with-alpha-importins
#14
Katharina Gerth, Feng Lin, Franziska Daamen, Wilhelm Menzel, Franziska Heinrich, Mareike Heilmann
The Arabidopsis phosphoinositide kinase PIP5K2 has been implicated in the control of membrane trafficking and is important for development and growth. In addition to cytosolic functions of phosphoinositides, a nuclear phosphoinositide system has been proposed, but evidence for nuclear phosphoinositides in plants is limited. Fluorescence-tagged variants of PIP5K2 reside in the nucleus of Arabidopsis root meristem cells, in addition to reported plasma membrane localization. Here we report on the interaction of PIP5K2 with alpha-importins and characterize its nuclear localization sequences (NLSs)...
September 26, 2017: Plant Journal: for Cell and Molecular Biology
https://www.readbyqxmd.com/read/28942281/antihypertrophic-effects-of-small-molecules-that-maintain-mitochondrial-atp-levels-under-hypoxia
#15
Hiroaki Nagai, Tomoko Satomi, Akiko Abiru, Kazumasa Miyamoto, Koji Nagasawa, Minoru Maruyama, Satoshi Yamamoto, Kuniko Kikuchi, Hiromitsu Fuse, Masakuni Noda, Yoshiyuki Tsujihata
Since impaired mitochondrial ATP production in cardiomyocytes is thought to lead to heart failure, a drug that protects mitochondria and improves ATP production under disease conditions would be an attractive treatment option. In this study, we identified small-molecule drugs, including the anti-parasitic agent, ivermectin, that maintain mitochondrial ATP levels under hypoxia in cardiomyocytes. Mechanistically, transcriptomic analysis and gene silencing experiments revealed that ivermectin increased mitochondrial ATP production by inducing Cox6a2, a subunit of the mitochondrial respiratory chain...
October 2017: EBioMedicine
https://www.readbyqxmd.com/read/28939615/regulation-of-mitotic-spindle-assembly-factor-numa-by-importin-%C3%AE
#16
Chih-Chia Chang, Tzu-Lun Huang, Yuta Shimamoto, Su-Yi Tsai, Kuo-Chiang Hsia
Ran-guanosine triphosphatase orchestrates mitotic spindle assembly by modulation of the interaction between Importin-α/-β and spindle assembly factors (SAFs). The inhibition of SAFs performed by importins needs to be done without much sequestration from abundant nuclear localization signal (NLS) -containing proteins. However, the molecular mechanisms that determine NLS-binding selectivity and that inhibit activity of Importin-β-regulated SAFs (e.g., nuclear mitotic apparatus protein [NuMA]) remain undefined...
November 6, 2017: Journal of Cell Biology
https://www.readbyqxmd.com/read/28931593/active-ran-regulates-anillin-function-during-cytokinesis
#17
Daniel Beaudet, Tara Akhshi, Julia Phillipp, Christopher Law, Alisa Piekny
Cytokinesis cleaves a cell into two daughters at the end of mitosis, and must be spatially coordinated with chromosome segregation to prevent aneuploidy. The dogma is that the mitotic spindle governs the assembly and constriction of an actomyosin ring. Here, we reveal a function for active Ran in spatially restricting the ring. Our model is that during anaphase, 'free' importins, whose gradient inversely correlates with active Ran and chromatin position, function as a molecular ruler for the recruitment and localization of anillin, a contractile protein and crucial regulator of cytokinesis...
September 20, 2017: Molecular Biology of the Cell
https://www.readbyqxmd.com/read/28930673/pexrap-inhibits-prdm16-mediated-thermogenic-gene-expression
#18
Irfan J Lodhi, John M Dean, Anyuan He, Hongsuk Park, Min Tan, Chu Feng, Haowei Song, Fong-Fu Hsu, Clay F Semenkovich
How the nuclear receptor PPARγ regulates the development of two functionally distinct types of adipose tissue, brown and white fat, as well as the browning of white fat, remains unclear. Our previous studies suggest that PexRAP, a peroxisomal lipid synthetic enzyme, regulates PPARγ signaling and white adipogenesis. Here, we show that PexRAP is an inhibitor of brown adipocyte gene expression. PexRAP inactivation promoted adipocyte browning, increased energy expenditure, and decreased adiposity. Identification of PexRAP-interacting proteins suggests that PexRAP function extends beyond its role as a lipid synthetic enzyme...
September 19, 2017: Cell Reports
https://www.readbyqxmd.com/read/28920551/a-comprehensive-in-silico-analysis-of-huntingtin-and-its-interactome
#19
Valentina Brandi, Valentina Di Lella, Maria Marino, Paolo Ascenzi, Fabio Polticelli
A polyglutamine expansion of the N-terminal region of huntingtin (Htt) causes Huntington's disease (HD), a severe neurodegenerative disorder. Htt huge multidomain structure, the presence of disordered regions, and the lack of sequence homologs of known structure, so far prevented structural studies of Htt, making the study of its structure-function relationships very difficult. In this work, the presence and location of five Htt ordered domains (named from Hunt1 to Hunt5) has been detected and the structure of these domains has been predicted for the first time using a combined threading/ab initio modelling approach...
September 18, 2017: Journal of Biomolecular Structure & Dynamics
https://www.readbyqxmd.com/read/28915577/vorinostat-suppresses-hypoxia-signaling-by-modulating-nuclear-translocation-of-hypoxia-inducible-factor-1-alpha
#20
Chao Zhang, Chunzhang Yang, Michael J Feldman, Herui Wang, Ying Pang, Dominic M Maggio, Dongwang Zhu, Cody L Nesvick, Pauline Dmitriev, Petra Bullova, Prashant Chittiboina, Roscoe O Brady, Karel Pacak, Zhengping Zhuang
Histone deacetylase inhibitors (HDACis) are a potent class of tumor-suppressive agents traditionally believed to exert their effects through loosening tightly-wound chromatin resulting in de-inhibition of various tumor suppressive genes. Recent literature however has shown altered intratumoral hypoxia signaling with HDACi administration not attributable to changes in chromatin structure. We sought to determine the precise mechanism of HDACi-mediated hypoxia signaling attenuation using vorinostat (SAHA), an FDA-approved class I/IIb/IV HDACi...
August 22, 2017: Oncotarget
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