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Sailen Barik
The two classical immunophilin families, found essentially in all living cells, are: cyclophilin (CYN) and FK506-binding protein (FKBP). We previously reported a novel class of immunophilins that are natural chimera of these two, which we named dual-family immunophilin (DFI). The DFIs were found in either of two conformations: CYN-linker-FKBP (CFBP) or FKBP-3TPR-CYN (FCBP). While the 3TPR domain can serve as a flexible linker between the FKBP and CYN modules in the FCBP-type DFI, the linker sequences in the CFBP-type DFIs are relatively short, diverse in sequence, and contain no discernible motif or signature...
2018: Computational and Structural Biotechnology Journal
Yibin Hao, Jianhua Zhang, Guoyong Shan, Ning Zhang, Wenwen Jin, Kejun Nan
Objective: to establish regulatory network of colorectal cancer involving p42.3 protein and to provide theoretical evidence for deep functional exploration of p42.3 protein in the onset and development of colorectal cancer. Methods: with protein similarity algorithm, reference protein set of p42.3 cell apoptosis was built according to structural features of p42.3. GO and KEGG databases were used to establish regulatory network of tumor cell apoptosis involving p42.3; meanwhile, the largest possible working pathway that involves p42...
December 2017: Saudi Journal of Biological Sciences
Nicole A Becker, Tanya L Schwab, Karl J Clark, L James Maher
Genetic switches must alternate between states whose probabilities are dependent on regulatory signals. Classical examples of transcriptional control in bacteria depend on repressive DNA loops anchored by proteins whose structures are sensitive to small molecule inducers or co-repressors. We are interested in exploiting these natural principles to engineer artificial switches for transcriptional control of bacterial genes. Here, we implement designed homodimeric DNA looping proteins ('Transcription Activator-Like Effector Dimers'; TALEDs) for this purpose in living bacteria...
January 30, 2018: Nucleic Acids Research
Mayra Delgado-Ramírez, José J De Jesús-Pérez, Iván A Aréchiga-Figueroa, Jorge Arreola, Scott K Adney, Carlos A Villalba-Galea, Diomedes E Logothetis, Aldo A Rodríguez-Menchaca
Phosphatidylinositol 4,5-bisphosphate (PIP2) is a membrane phospholipid that regulates the function of multiple ion channels, including some members of the voltage-gated potassium (Kv) channel superfamily. The PIP2 sensitivity of Kv channels is well established for all five members of the Kv7 family and for Kv1.2 channels; however, regulation of other Kv channels by PIP2 remains unclear. Here, we investigate the effects of PIP2 on Kv2.1 channels by applying exogenous PIP2 to the cytoplasmic face of excised membrane patches, activating muscarinic receptors (M1R), or depleting endogenous PIP2 using a rapamycin-translocated 5-phosphatase (FKBP-Inp54p)...
January 29, 2018: Scientific Reports
David Dilworth, Geoff Gudavicius, Xiaoxue Xu, Andrew K J Boyce, Connor O'Sullivan, Jason J Serpa, Misha Bilenky, Evgeniy V Petrochenko, Christoph H Borchers, Martin Hirst, Leigh Anne Swayne, Perry Howard, Christopher J Nelson
FK506 binding proteins (FKBPs) catalyze the interconversion of cis-trans proline conformers in proteins. Importantly, FK506 drugs have anti-cancer and neuroprotective properties, but the effectors and mechanisms underpinning these properties are not well understood because the cellular function(s) of most FKBP proteins are unclear. FKBP25 is a nuclear prolyl isomerase that interacts directly with nucleic acids and is associated with several DNA/RNA binding proteins. Here, we show the catalytic FKBP domain binds microtubules (MTs) directly to promote their polymerization and stabilize the MT network...
January 18, 2018: Nucleic Acids Research
Andrea Martins-da-Silva, Erich Loza Telleria, Michel Batista, Fabricio Klerynton Marchini, Yara Maria Traub-Csekö, Antonio Jorge Tempone
Hematophagous insects transmit infectious diseases. Sand flies are vectors of leishmaniasis, but can also transmit viruses. We have been studying immune responses of Lutzomyia longipalpis, the main vector of visceral leishmaniasis in the Americas. We identified a non-specific antiviral response in L. longipalpis LL5 embryonic cells when treated with non-specific double-stranded RNAs (dsRNAs). This response is reminiscent of interferon response in mammals. We are investigating putative effectors for this antiviral response...
January 18, 2018: Viruses
Carolin Schmelas, Dirk Grimm
The discovery that the bacterial CRISPR/Cas9 system can be translated into mammalian cells continues to have an unprecedented impact on the biomedical research community, as it largely facilitates efforts to experimentally interrogate or therapeutically modify the cellular genome. In particular, CRISPR promises the ability to correct disease-associated genetic defects, or to target and destroy invading foreign DNA, in a simple, efficient, and selective manner directly in affected human cells or tissues. Here, we highlight a set of exciting new strategies that aim at further increasing the therapeutic index of CRISPR technologies, by reducing the size of Cas9 expression cassettes and thus enhancing their compatibility with viral gene delivery vectors...
January 5, 2018: Biotechnology Journal
Yasuyuki Honjo, Takashi Ayaki, Tomohisa Horibe, Hidefumi Ito, Ryosuke Takahashi, Koji Kawakami
α-Synuclein (α-SYN), a presynaptic protein with the tendency to aggregate, is linked to α-synucleinopathies such as Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA). α-SYN is the main component of round intracytoplasmic inclusions called Lewy bodies (LBs), which are the hallmark of PD and DLB. In addition, accumulation of amyloid-β and neurofibrillary tangles as in the pathology of Alzheimer's disease has been found in the DLB brain. Glial cytoplasmic inclusions are an MSA-specific type of inclusion found in oligodendrocytes and mainly comprise α-SYN...
December 12, 2017: Brain Research
Gabriel R Fries, Nils C Gassen, Theo Rein
Among the chaperones and co-chaperones regulating the glucocorticoid receptor (GR), FK506 binding protein (FKBP) 51 is the most intensely investigated across different disciplines. This review provides an update on the role of the different co-chaperones of Hsp70 and Hsp90 in the regulation of GR function. The development leading to the focus on FKBP51 is outlined. Further, a survey of the vast literature on the mechanism and function of FKBP51 is provided. This includes its structure and biochemical function, its regulation on different levels-transcription, post-transcription, and post-translation-and its function in signaling pathways...
December 5, 2017: International Journal of Molecular Sciences
Hwei Ling Tan, Kim Kiat Lim, Qiaoyun Yang, Jing-Song Fan, Ahmed Mahmoud Mohammed Sayed, Liy Sim Low, Bingbing Ren, Teck Kwang Lim, Qingsong Lin, Yu-Keung Mok, Yih-Cherng Liou, Ee Sin Chen
Centromeric identity and chromosome segregation are determined by the precise centromeric targeting of CENP-A, the centromere-specific histone H3 variant. The significance of the amino-terminal domain (NTD) of CENP-A in this process remains unclear. Here, we assessed the functional significance of each residue within the NTD of CENP-A from Schizosaccharomyces pombe (SpCENP-A) and identified a proline-rich 'GRANT' (Genomic stability-Regulating site within CENP-A N-Terminus) motif that is important for CENP-A function...
February 16, 2018: Nucleic Acids Research
Anne-Juliane Geitner, Ulrich Weininger, Hauke Paulsen, Jochen Balbach, Michael Kovermann
SlpA (SlyD-like protein A) comprises two domains, a FK506 binding domain (FKBP fold) of moderate prolyl cis/trans-isomerase activity and an inserted in flap (IF) domain that hosts its chaperone activity. Here we present the nuclear magnetic resonance (NMR) solution structure of apo Escherichia coli SlpA determined by NMR that mirrors the structural properties seen for various SlyD homologues. Crucial structural differences in side-chain orientation arise for F37, which points directly into the hydrophobic core of the active site...
December 19, 2017: Biochemistry
Yanmei Zhu, Yuehua Gong, Aodi Li, Moye Chen, Dan Kang, Jun Liu, Yuan Yuan
PURPOSE: Though Helicobacter pylori (H. pylori) has been classified as class I carcinogen, key virulence factor generated by H. pylori that causes gastric cancer remains to be fully determined. Recently, we identified a gastric cancer-associated H. pylori gene, peptidylprolyl isomerase-FK506 binding protein (PPIase-FKBP), and showed that PPIase-FKBP was capable of inducing oncogenic transformation of gastric epithelial cells. But its mechanism was unclear. EXPERIMENTAL DESIGN: We carried out a comparative proteomic analysis of human gastric epithelial cells that either express PPIase-FKBP or green fluorescent protein using 2-DE and then MALDI-TOF-MS/MS...
November 16, 2017: Proteomics. Clinical Applications
Shuying Li, Zhanjun Liu, Ji Li, Aihua Liu, Lihua Zhu, Kui Yu, Ke Zhang
The present study aimed to explore the effects of a stabilizing ligand, Shield‑1, on the replication of recombinant varicella‑zoster virus (VZV) containing FK506 binding protein (FKPB) tags in essential open reading frames (ORF) 4 and 48. A specific galactokinase (galK) selection method was conducted, following the addition of galK labels to VZV ORF4 and 48, using a SW102 VZV bacterial artificial chromosome (BAC) system. Subsequently, recombinant VZV containing FKPB tags in ORF4 and 48 was constructed by counterselection and homologous recombination...
January 2018: Molecular Medicine Reports
Jugal P Dhandhukia, Zhe Li, Santosh Peddi, Shruti Kakan, Arjun Mehta, David Tyrpak, Jordan Despanie, J Andrew MacKay
Recombinant Elastin-Like Polypeptides (ELPs) serve as attractive scaffolds for nanoformulations because they can be charge-neutral, water soluble, high molecular weight, monodisperse, biodegradable, and decorated with functional proteins. We recently reported that fusion of the FK-506 binding protein 12 (FKBP) to an ELP nanoparticle (FSI) reduces rapamycin (Rapa) toxicity and enables intravenous (IV) therapy in both a xenograft breast cancer model and a murine autoimmune disease model. Rapa has poor solubility, which leads to variable oral bioavailability or drug precipitation following parenteral administration...
2017: Theranostics
Kyle V Butler, Anna M Chiarella, Jian Jin, Nathaniel A Hathaway
Epigenome editing is a powerful method for life science research and could give rise to new therapies for diseases initiated or maintained by epigenetic dysregulation, including several types of cancers and autoimmune disorders. In addition, much is still unknown about the mechanisms by which histone-modifying proteins work in concert to properly regulate gene expression. To investigate and manipulate complex epigenetic interactions in live cells, we have developed a small molecule platform for specifically inducing gene repression and histone deacetylation at a reporter gene...
November 7, 2017: ACS Synthetic Biology
Catherine B Carbone, Nadja Kern, Ricardo A Fernandes, Enfu Hui, Xiaolei Su, K Christopher Garcia, Ronald D Vale
T cell signaling initiates upon the binding of peptide-loaded MHC (pMHC) on an antigen-presenting cell to the T cell receptor (TCR) on a T cell. TCR phosphorylation in response to pMHC binding is accompanied by segregation of the transmembrane phosphatase CD45 away from TCR-pMHC complexes. The kinetic segregation hypothesis proposes that CD45 exclusion shifts the local kinase-phosphatase balance to favor TCR phosphorylation. Spatial partitioning may arise from the size difference between the large CD45 extracellular domain and the smaller TCR-pMHC complex, although parsing potential contributions of extracellular protein size, actin activity, and lipid domains is difficult in living cells...
October 31, 2017: Proceedings of the National Academy of Sciences of the United States of America
David Dilworth, Santosh K Upadhyay, Pierre Bonnafous, Amiirah Bibi Edoo, Sarah Bourbigot, Francy Pesek-Jardim, Geoff Gudavicius, Jason J Serpa, Evgeniy V Petrotchenko, Christoph H Borchers, Christopher J Nelson, Cameron D Mackereth
Prolyl isomerases are defined by a catalytic domain that facilitates the cis-trans interconversion of proline residues. In most cases, additional domains in these enzymes add important biological function, including recruitment to a set of protein substrates. Here, we report that the N-terminal basic tilted helix bundle (BTHB) domain of the human prolyl isomerase FKBP25 confers specific binding to double-stranded RNA (dsRNA). This binding is selective over DNA as well as single-stranded oligonucleotides. We find that FKBP25 RNA-association is required for its nucleolar localization and for the vast majority of its protein interactions, including those with 60S pre-ribosome and early ribosome biogenesis factors...
November 16, 2017: Nucleic Acids Research
José-Carlos Fernández-Morales, Martin Morad
Ischemic heart disease is an arrhythmogenic condition, accompanied by hypoxia, acidosis, and impaired Ca2+ signaling. Here we report on effects of acute hypoxia and acidification in rat neonatal cardiomyocytes cultures. RESULTS: Two populations of neonatal cardiomyocyte were identified based on inactivation kinetics of L-type ICa : rapidly-inactivating ICa (τ~20ms) myocytes (prevalent in 3-4-day cultures), and slow-inactivating ICa (τ≥40ms) myocytes (dominant in 7-day cultures). Acute hypoxia (pO2 <5mmHg for 50-100s) suppressed ICa reversibly in both cell-types to different extent and with different kinetics...
January 2018: Journal of Molecular and Cellular Cardiology
Maristella De Cicco, Lech-G Milroy, Sonja A Dames
Increased efforts have been undertaken to better understand the formation of signaling complexes at cellular membranes. Since the preparation of proteins containing a transmembrane domain or a prenylation motif is generally challenging an alternative membrane anchoring unit that is easy to attach, water-soluble and binds to different membrane mimetics would find broad application. The 33-residue long FATC domain of yeast TOR1 (y1fatc) fulfills these criteria and binds to neutral and negatively charged micelles, bicelles and liposomes...
October 12, 2017: Protein Science: a Publication of the Protein Society
Spencer J Richardson, Gregory A Steele, Esther M Gallant, Alexander Lam, Charles E Schwartz, Philip G Board, Marco G Casarotto, Nicole A Beard, Angela F Dulhunty
No abstract text is available yet for this article.
October 5, 2017: Journal of Cell Science
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