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Unstructured Proteins

Jeffrey D Levengood, Blanton S Tolbert
The heterogeneous nuclear ribonucleoproteins (hnRNPs) are a diverse family of RNA binding proteins that function in most stages of RNA metabolism. The prototypical member, hnRNP A1, is composed of three major domains; tandem N-terminal RNA Recognition Motifs (RRMs) and a C-terminal mostly intrinsically disordered region. HnRNP A1 is broadly implicated in basic cellular RNA processing events such as splicing, stability, nuclear export and translation. Due to its ubiquity and abundance, hnRNP A1 is also frequently usurped to control viral gene expression...
April 3, 2018: Seminars in Cell & Developmental Biology
Michele Vitali, Valentina Rigamonti, Antonino Natalello, Barbara Colzani, Svetlana Avvakumova, Stefania Brocca, Carlo Santambrogio, Joanna Narkiewicz, Giuseppe Legname, Miriam Colombo, Davide Prosperi, Rita Grandori
BACKGROUND: Protein-nanoparticle (NP) interactions dictate properties of nanoconjugates relevant for bionanotechnology. Non-covalent adsorption generates a protein corona (PC) formed by an inner and an outer layer, the hard and soft corona (HC, SC). Intrinsically disordered proteins (IDPs) exist in solution as conformational ensembles, whose features in the presence of NPs are not well known. METHODS: Three IDPs (α-casein, Sic1 and α-synuclein) and lysozyme are compared, describing conformational properties inside HC on silica NPs by circular dichroism (CD) and Fourier-transform infrared (FTIR) spectroscopy...
April 2, 2018: Biochimica et Biophysica Acta
Tesmine Martin, Yuan-Chao Lou, Chun-Chi Chou, Shu-Yi Wei, Sushant Sadotra, Chao-Cheng Cho, Meng-Hsuan Lin, Jung-Hsiang Tai, Chun-Hua Hsu, Chinpan Chen
Cyclophilin 1 (TvCyP1), a cyclophilin type peptidyl-prolyl isomerase present in the human parasite Trichomonas vaginalis, interacts with Myb1 and assists in its nuclear translocation. Myb1 regulates the expression of ap65-1 gene that encodes for a disease causing cytoadherence enzyme. Here, we determined the crystal structures of TvCyP1 and its complex with the minimum TvCyP1-binding sequence of Myb1 (Myb1104-111 ), where TvCyP1 formed a homodimer, unlike other single domain cyclophilins. In the complex structure, one Myb1104-111 peptide was bound to each TvCyP1 protomer, with G106-P107 and Y105 fitting well into the active site and auxiliary S2 pocket, respectively...
April 3, 2018: Scientific Reports
Ines Reinartz, Claude Sinner, Daniel Nettels, Brigitte Stucki-Buchli, Florian Stockmar, Pawel T Panek, Christoph R Jacob, Gerd Ulrich Nienhaus, Benjamin Schuler, Alexander Schug
Fully understanding biomolecular function requires detailed insight into the systems' structural dynamics. Powerful experimental techniques such as single molecule Förster Resonance Energy Transfer (FRET) provide access to such dynamic information yet have to be carefully interpreted. Molecular simulations can complement these experiments but typically face limits in accessing slow time scales and large or unstructured systems. Here, we introduce a coarse-grained simulation technique that tackles these challenges...
March 28, 2018: Journal of Chemical Physics
Médoune Sarr, Nina Kronqvist, Gefei Chen, Rihards Aleksis, Pasi Purhonen, Hans Hebert, Kristaps Jaudzems, Anna Rising, Jan Johansson
Amyloidogenesis is associated with more than 30 diseases but the molecular mechanisms involved in cell toxicity and fibril formation remain largely unknown. The inherent tendency of amyloid-forming proteins to aggregate renders expression, purification and experimental studies challenging. NT* is a solubility tag derived from a spider silk protein that was recently introduced for production of several aggregation-prone peptides and proteins at high yields. Herein, we investigate whether fusion to NT* can prevent amyloid fibril formation and enable controlled aggregation for experimental studies...
March 31, 2018: FEBS Journal
Giuliana Fusco, Maximo Sanz-Hernandez, Francesco S Ruggeri, Michele Vendruscolo, Christopher M Dobson, Alfonso De Simone
The aggregation process of peptides and proteins is of great relevance as it is associated with a wide range of highly debilitating disorders, including Alzheimer's and Parkinson's diseases. The natural product (-)-epigallocatechin-3-gallate (EGCG) can redirect this process away from amyloid fibrils and towards non-toxic oligomers. In this study we used nuclear magnetic resonance (NMR) spectroscopy to characterize the binding of EGCG to a set of natively structured and unstructured proteins. The results show that the binding process is dramatically dependent on the conformational properties of the protein involved, as EGCG interacts with different binding modes depending on the folding state of the protein...
March 30, 2018: Biopolymers
Elena Rostkova, Selena G Burgess, Richard Bayliss, Mark Pfuhl
The microtubule regulatory protein colonic and hepatic tumor overexpressed gene (chTOG), also known as cytoskeleleton associated protein 5 (CKAP5) plays an important role in organizing the cytoskeleton and in particular in the assembly of k-fibres in mitosis. Recently, we dissected the hitherto poorly understood C-terminus of this protein by discovering two new domains-a cryptic TOG domain (TOG6) and a smaller, helical domain at the very C-terminus. It was shown that the C-terminal domain is important for the interaction with the TACC domain in TACC3 during the assembly of k-fibres in a ternary complex that also includes clathrin...
March 26, 2018: Biomolecular NMR Assignments
Anselm Gruber, Daniel Hornburg, Matthias Antonin, Natalie Krahmer, Javier Collado, Miroslava Schaffer, Greta Zubaite, Christian Lüchtenborg, Timo Sachsenheimer, Britta Brügger, Matthias Mann, Wolfgang Baumeister, F Ulrich Hartl, Mark S Hipp, Rubén Fernández-Busnadiego
Huntington's disease is caused by the expansion of a polyglutamine (polyQ) tract in the N-terminal exon of huntingtin (HttEx1), but the cellular mechanisms leading to neurodegeneration remain poorly understood. Here we present in situ structural studies by cryo-electron tomography of an established yeast model system of polyQ toxicity. We find that expression of polyQ-expanded HttEx1 results in the formation of unstructured inclusion bodies and in some cases fibrillar aggregates. This contrasts with recent findings in mammalian cells, where polyQ inclusions were exclusively fibrillar...
March 26, 2018: Proceedings of the National Academy of Sciences of the United States of America
Benjamin Fritch, Andrey Kosolapov, Phillip S Hudson, Daniel A Nissley, H Lee Woodcock, Carol Deutsch, Edward P O'Brien
Mechanical forces acting on the ribosome can alter the speed of protein synthesis, indicating that mechanochemistry can contribute to translation control of gene expression. The naturally occurring sources of these mechanical forces, the mechanism by which they are transmitted 10 nm to the ribosome's catalytic core, and how they influence peptide bond formation rates are largely unknown. Here, we identify a new source of mechanical force acting on the ribosome by using in situ experimental measurements of changes in nascent-chain extension in the exit tunnel in conjunction with all-atom and coarse-grained computer simulations...
March 26, 2018: Journal of the American Chemical Society
Nesly Dotan, Vera Gayder, Itai Bloch, Maayan Gal
Calcineurin is a phosphatase that targets the transcription factor, nuclear factor of activated T-cells (NFAT) dephosphorylates multiple sites along NFAT's regulatory domain. The calcineurin-NFAT complex interaction is mediated through two conserved binding motifs known as the PxIxIT and LxVP, which are located at the N- and C- terminus to the phosphorylation sites. The vast range of cellular processes regulated by the calcineurin-NFAT interaction has aroused great interest in the investigation of the structural aspects that govern their complex formation and in the discovery of protein-protein interaction inhibitors; the latter interfere with calcineurin-NFAT complex formation while keeping calcineurin's catalytic site free...
March 16, 2018: Analytical Biochemistry
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
A D Nikulin
This review is focused on the structural aspects of interaction between ribosomal proteins and ribosomal RNA in bacterial ribosomes and complexes of ribosomal proteins with specific fragments of ribosomal RNA. Special attention is given to the recognition of specific spatial architecture of the double-stranded ribosomal RNA by ribosomal proteins and to the role of unstructured protein regions in stabilization of distant ribosomal RNA segments.
January 2018: Biochemistry. Biokhimii︠a︡
Andrew J Olsen, Priya Katyal, Jennifer S Haghpanah, Matthew B Kubilius, Ruipeng Li, Nicole L Schnabel, Sean C O'Neill, Yao Wang, Min Dai, Navjot Singh, Raymond S Tu, Jin Kim Montclare
Recombinant methods have been used to engineer artificial protein triblock polymers comprised of two different self-assembling domains (SADs) bearing one elastin (E) flanked by two cartilage oligomeric matrix protein coiled-coil (C) domains to generate CEC. To understand how the two C domains improve small molecule recognition and the mechanical integrity of CEC, we have constructed CL44AECL44A, which bears an impaired CL44A domain that is unstructured as a negative control. The CEC triblock polymer demonstrates increased small molecule binding and ideal elastic behavior for hydrogel formation...
March 15, 2018: Biomacromolecules
Angelina D Schoenenberger, Jasper Foolen, Pascal Moor, Unai Silvan, Jess G Snedeker
Healthy tendon tissue features a highly aligned extracellular matrix that becomes disorganized with disease. Recent evidence suggests that inflammation coexists with early degenerative changes in tendon, and that crosstalk between immune-cells and tendon fibroblasts (TFs) can contribute to poor tissue healing. We hypothesized that a disorganized tissue architecture may predispose tendon cells to degenerative extracellular matrix remodeling pathways, particularly within a pro-inflammatory niche. This hypothesis was tested by analyzing human TFs cultured on electrospun polycaprolactone (PCL) mats with either highly aligned or randomly oriented fiber structures...
March 9, 2018: Acta Biomaterialia
Fabian Paul, Frank Noé, Thomas R Weikl
Unstructured protein and peptides typically fold during binding to ligand proteins. A challenging problem is to identify the mechanism and kinetics of these binding-induced folding processes in experiments and atomistic simulations. In this article, we present a detailed picture for the folding of the inhibitor peptide PMI into a helix during binding to the oncoprotein fragment25-109 Mdm2 obtained from atomistic, explicit-water simulations and Markov state modeling. We find that binding-induced folding of PMI is highly parallel and can occur along a multitude of pathways...
March 9, 2018: Journal of Physical Chemistry. B
Ignacio Hugo Castro, Alejandro Ferrari, María Georgina Herrera, Martín Ezequiel Noguera, Lorenzo Maso, Monica Benini, Alessandra Rufini, Roberto Testi, Paola Costantini, Javier Santos
Friedreich's ataxia is a disease caused by a decrease in the levels of expression or loss of functionality of the mitochondrial protein frataxin (FXN). The development of an active and stable recombinant variant of FXN is important for protein replacement therapy. Although valuable data about the mature form FXN81-210 has been collected, not enough information is available about the conformation of the frataxin precursor (FXN1-210). We investigated the conformation, stability and function of a recombinant precursor variant (His6-TAT-FXN1-210), which includes a TAT peptide in the N-terminal region to assist with transport across cell membranes...
March 2018: FEBS Open Bio
David Corujo, Marcus Buschbeck
Histone variants are chromatin components that replace replication-coupled histones in a fraction of nucleosomes and confer particular characteristics to chromatin. H2A variants represent the most numerous and diverse group among histone protein families. In the nucleosomal structure, H2A-H2B dimers can be removed and exchanged more easily than the stable H3-H4 core. The unstructured N-terminal histone tails of all histones, but also the C-terminal tails of H2A histones protrude out of the compact structure of the nucleosome core...
February 27, 2018: Cancers
Radhika P Nagarkar, Stephen E Miller, Sheng Zhong, Darrin J Pochan, Joel P Schneider
The repetitive self-assembled structure of amyloid can serve as inspiration to design functional materials. Herein, we describe the design of α/β6, a peptide that contains distinct α-helical and β-structure forming domains. The folding and association state of each domain can be controlled by temperature. At low temperatures, the α-domain favors a coiled coil state while the β-domain is unstructured. Irreversible fibril formation via self-assembly of the β-domain is triggered at high temperatures where the α-domain is unfolded...
March 1, 2018: Protein Science: a Publication of the Protein Society
Huachuan Du, Alice Cont, Mathias Steinacher, Esther Amstad
Natural soft materials are often composed of proteins that self-assemble into well-defined structures and display mechanical properties that cannot be matched by manmade materials. These materials are frequently mimicked with hydrogels whose mechanical properties depend on their composition and the type and density of crosslinks. Protocols to tune these parameters are well established and routinely used. The mechanical properties of hydrogels also depend on their structure; this parameter is more difficult to control...
February 28, 2018: Langmuir: the ACS Journal of Surfaces and Colloids
Apoorva Verma, Fan Jing-Song, Megan L Finch-Edmondson, Adrian Velazquez-Campoy, Shanker Balasegaran, Marius Sudol, Jayaraman Sivaraman
YES-associated protein (YAP) is a major effector protein of the Hippo tumor suppressor pathway, and is phosphorylated by the serine/threonine kinase LATS. Their binding is mediated by the interaction between WW domains of YAP and PPxY motifs of LATS. Their isoforms, YAP2 and LATS1 contain two WW domains and two PPxY motifs respectively. Here, we report the study of the interaction of these domains both in vitro and in human cell lines, to better understand the mechanism of their binding. We show that there is a reciprocal binding preference of YAP2-WW1 with LATS1-PPxY2, and YAP2-WW2 with LATS1-PPxY1...
January 30, 2018: Oncotarget
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