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Unstructured Proteins

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https://www.readbyqxmd.com/read/28230082/tubz-filament-assembly-dynamics-requires-the-flexible-c-terminal-tail
#1
Maria E Fuentes-Pérez, Rafael Núñez-Ramírez, Alejandro Martín-González, David Juan-Rodríguez, Oscar Llorca, Fernando Moreno-Herrero, Maria A Oliva
Cytomotive filaments are essential for the spatial organization in cells, showing a dynamic behavior based on nucleotide hydrolysis. TubZ is a tubulin-like protein that functions in extrachromosomal DNA movement within bacteria. TubZ filaments grow in a helical fashion following treadmilling or dynamic instability, although the underlying mechanism is unclear. We have unraveled the molecular basis for filament assembly and dynamics combining electron and atomic force microscopy and biochemical analyses. Our findings suggest that GTP caps retain the filament helical structure and hydrolysis triggers filament stiffening upon disassembly...
February 23, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28218748/hiv-tat-protein-and-amyloid-%C3%AE-peptide-form-multifibrillar-structures-that-cause-neurotoxicity
#2
Alina Hategan, Mario A Bianchet, Joseph Steiner, Elena Karnaukhova, Eliezer Masliah, Adam Fields, Myoung-Hwa Lee, Alex M Dickens, Norman Haughey, Emilios K Dimitriadis, Avindra Nath
Deposition of amyloid-β plaques is increased in the brains of HIV-infected individuals, and the HIV transactivator of transcription (Tat) protein affects amyloidogenesis through several indirect mechanisms. Here, we investigated direct interactions between Tat and amyloid-β peptide. Our in vitro studies showed that in the presence of Tat, uniform amyloid fibrils become double twisted fibrils and further form populations of thick unstructured filaments and aggregates. Specifically, Tat binding to the exterior surfaces of the Aβ fibrils increases β-sheet formation and lateral aggregation into thick multifibrillar structures, thus producing fibers with increased rigidity and mechanical resistance...
February 20, 2017: Nature Structural & Molecular Biology
https://www.readbyqxmd.com/read/28214511/identification-of-a-degradation-signal-sequence-within-substrates-of-the-mitochondrial-i-aaa-protease
#3
Anthony J Rampello, Steven E Glynn
The i-AAA protease is a component of the mitochondrial quality control machinery that regulates respiration, mitochondrial dynamics, and protein import. The protease is required to select specific substrates for degradation from among the diverse complement of proteins present in mitochondria, yet the rules that govern this selection are unclear. Here, we reconstruct the yeast i-AAA protease, Yme1p, to examine the in vitro degradation of two intermembrane space chaperone subunits, Tim9 and Tim10. Yme1p degrades Tim10 more rapidly than Tim9 despite high sequence and structural similarity, and loss of Tim10 is accelerated by disruption of conserved disulfide bonds within the substrate...
February 15, 2017: Journal of Molecular Biology
https://www.readbyqxmd.com/read/28196861/molecular-determinants-of-the-n-terminal-acetyltransferase-naa60-anchoring-to-the-golgi-membrane
#4
Henriette Aksnes, Marianne Goris, Øyvind Strømland, Adrian Drazic, Qaiser Waheed, Nathalie Reuter, Thomas Arnesen
Nα-acetyltransferase 60 (Naa60 or NatF) was recently identified as an unconventional N-terminal acetyltransferase (NAT) since it localizes to organelles, in particular the Golgi apparatus, and has a preference for acetylating N-termini of transmembrane proteins. This knowledge challenged the prevailing view of N-terminal acetylation as a co-translational ribosome-associated process and suggested a new mechanistic functioning for the enzymes responsible for this increasingly recognized protein modification...
February 14, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28185903/the-thermodynamics-of-protein-aggregation-reactions-may-underpin-the-enhanced-metabolic-efficiency-associated-with-heterosis-some-balancing-selection-and-the-evolution-of-ploidy-levels
#5
REVIEW
B R Ginn
Identifying the physical basis of heterosis (or "hybrid vigor") has remained elusive despite over a hundred years of research on the subject. The three main theories of heterosis are dominance theory, overdominance theory, and epistasis theory. Kacser and Burns (1981) identified the molecular basis of dominance, which has greatly enhanced our understanding of its importance to heterosis. This paper aims to explain how overdominance, and some features of epistasis, can similarly emerge from the molecular dynamics of proteins...
February 6, 2017: Progress in Biophysics and Molecular Biology
https://www.readbyqxmd.com/read/28179526/a-sequence-independent-unstructured-ires-is-responsible-for-internal-expression-of-the-coat-protein-of-turnip-crinkle-virus
#6
Jared May, Philip Johnson, Huma Saleem, Anne E Simon
To maximize the coding potential of viral genomes, internal ribosome entry sites (IRES) can be used to bypass the traditional requirement of a 5' cap and some/all of the associated translation initiation factors. Although viral IRES typically contain higher order RNA structure, an unstructured sequence of about 84-nt immediately upstream of the Turnip crinkle virus (TCV) coat protein (CP) ORF has been found to promote internal expression of the CP from the genomic (g)RNA both in vitro and in vivo Absence of extensive RNA structure was predicted using RNA folding algorithms and confirmed by SHAPE structure probing...
February 8, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28157327/discrete-molecular-dynamics-approach-to-the-study-of-disordered-and-aggregating-proteins
#7
Agustí Emperador, Modesto Orozco
We present a refinement of the Coarse Grained PACSAB force field for Discrete Molecular Dynamics (DMD) simulations of proteins in aqueous conditions. As the original version, the refined method provides good representation of the structure and dynamics of folded proteins but provides much better representations of a variety of unfolded proteins, including some very large, impossible to analyze by atomistic simulation methods. The PACSAB/DMD method also reproduces accurately aggregation properties, providing good pictures of the structural ensembles of proteins showing a folded core and an intrinsically disordered region...
February 15, 2017: Journal of Chemical Theory and Computation
https://www.readbyqxmd.com/read/28143508/prokaryotic-ubiquitin-like-protein-remains-intrinsically-disordered-when-covalently-attached-to-proteasomal-target-proteins
#8
Jonas Barandun, Fred F Damberger, Cyrille L Delley, Juerg Laederach, Frédéric H T Allain, Eilika Weber-Ban
BACKGROUND: The post-translational modification pathway referred to as pupylation marks proteins for proteasomal degradation in Mycobacterium tuberculosis and other actinobacteria by covalently attaching the small protein Pup (prokaryotic ubiquitin-like protein) to target lysine residues. In contrast to the functionally analogous eukaryotic ubiquitin, Pup is intrinsically disordered in its free form. Its unfolded state allows Pup to adopt different structures upon interaction with different binding partners like the Pup ligase PafA and the proteasomal ATPase Mpa...
February 1, 2017: BMC Structural Biology
https://www.readbyqxmd.com/read/28139759/the-intervening-domain-from-mecp2-enhances-the-dna-affinity-of-the-methyl-binding-domain-and-provides-an-independent-dna-interaction-site
#9
Rafael Claveria-Gimeno, Pilar M Lanuza, Ignacio Morales-Chueca, Olga C Jorge-Torres, Sonia Vega, Olga Abian, Manel Esteller, Adrian Velazquez-Campoy
Methyl-CpG binding protein 2 (MeCP2) preferentially interacts with methylated DNA and it is involved in epigenetic regulation and chromatin remodelling. Mutations in MeCP2 are linked to Rett syndrome, the leading cause of intellectual retardation in girls and causing mental, motor and growth impairment. Unstructured regions in MeCP2 provide the plasticity for establishing interactions with multiple binding partners. We present a biophysical characterization of the methyl binding domain (MBD) from MeCP2 reporting the contribution of flanking domains to its structural stability and dsDNA interaction...
January 31, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28138522/the-activation-loop-of-pip5k-functions-as-a-membrane-sensor-essential-for-lipid-substrate-processing
#10
Aizhuo Liu, Dexin Sui, Dianqing Wu, Jian Hu
Phosphatidylinositol 4-phosphate 5-kinase (PIP5K), a representative member of the phosphatidylinositol phosphate kinase (PIPK) family, is a major enzyme that biosynthesizes the signaling molecule PI(4,5)P2 (phosphatidylinositol 4,5-bisphosphate) in eukaryotic cells. The stringent specificity toward lipid substrates and the high sensitivity to the membrane environment strongly suggest a membrane-sensing mechanism, but the underlying structural basis is still largely unknown. We present a nuclear magnetic resonance (NMR) study on a peptide commensurate with a PIP5K's activation loop, which has been reported to be a determinant of lipid substrate specificity and subcellular localization of PIP5K...
November 2016: Science Advances
https://www.readbyqxmd.com/read/28137577/analysis-of-translocation-competent-secretory-proteins-by-hdx-ms
#11
A Tsirigotaki, M Papanastasiou, M B Trelle, T J D Jørgensen, A Economou
Protein folding is an intricate and precise process in living cells. Most exported proteins evade cytoplasmic folding, become targeted to the membrane, and then trafficked into/across membranes. Their targeting and translocation-competent states are nonnatively folded. However, once they reach the appropriate cellular compartment, they can fold to their native states. The nonnative states of preproteins remain structurally poorly characterized since increased disorder, protein sizes, aggregation propensity, and the observation timescale are often limiting factors for typical structural approaches such as X-ray crystallography and NMR...
2017: Methods in Enzymology
https://www.readbyqxmd.com/read/28128355/epigallocatechin-3-gallate-preferentially-induces-aggregation-of-amyloidogenic-immunoglobulin-light-chains
#12
Manuel Hora, Martin Carballo-Pacheco, Benedikt Weber, Vanessa K Morris, Antje Wittkopf, Johannes Buchner, Birgit Strodel, Bernd Reif
Antibody light chain amyloidosis is a rare disease caused by fibril formation of secreted immunoglobulin light chains (LCs). The huge variety of antibody sequences puts a serious challenge to drug discovery. The green tea polyphenol epigallocatechin-3-gallate (EGCG) is known to interfere with fibril formation in general. Here we present solution- and solid-state NMR studies as well as MD simulations to characterise the interaction of EGCG with LC variable domains. We identified two distinct EGCG binding sites, both of which include a proline as an important recognition element...
January 27, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28120469/molecular-cross-talk-between-nonribosomal-peptide-synthetase-carrier-proteins-and-unstructured-linker-regions
#13
Bradley James Harden, Dominique P Frueh
Nonribosomal peptide synthetases (NRPSs) employ multiple domains separated by linker regions to incorporate substrates into natural products. During synthesis, substrates are covalently tethered to carrier proteins that translocate between catalytic partner domains. The molecular parameters that govern translocation and associated linker remodeling remain unknown. Here, we used NMR to characterize the structure, dynamics, and invisible states of a peptidyl carrier protein flanked by its linkers. We show that the N-terminal linker stabilizes and interacts with the protein core while modulating dynamics at specific sites involved in post-translational modifications and/or domain interactions...
January 24, 2017: Chembiochem: a European Journal of Chemical Biology
https://www.readbyqxmd.com/read/28114338/proteolysis-dependent-remodeling-of-the-tubulin-homolog-ftsz-at-the-division-septum-in-escherichia-coli
#14
Marissa G Viola, Christopher J LaBreck, Joseph Conti, Jodi L Camberg
During bacterial cell division a dynamic protein structure called the Z-ring assembles at the septum. The major protein in the Z-ring in Escherichia coli is FtsZ, a tubulin homolog that polymerizes with GTP. FtsZ is degraded by the two-component ATP-dependent protease ClpXP. Two regions of FtsZ, located outside of the polymerization domain in the unstructured linker and at the C-terminus, are important for specific recognition and degradation by ClpXP. We engineered a synthetic substrate containing green fluorescent protein (Gfp) fused to an extended FtsZ C-terminal tail (residues 317-383), including the unstructured linker and the C-terminal conserved region, but not the polymerization domain, and showed that it is sufficient to target a non-native substrate for degradation in vitro...
2017: PloS One
https://www.readbyqxmd.com/read/28109185/folding-of-intrinsically-disordered-plant-lea-proteins-is-driven-by-glycerol-induced-crowding-and-the-presence-of-membranes
#15
Anne Bremer, Martin Wolff, Anja Thalhammer, Dirk K Hincha
Late embryogenesis abundant (LEA) proteins are related to cellular dehydration tolerance. Most LEA proteins are predicted to have no stable secondary structure in solution, i.e., to be intrinsically disordered proteins (IDPs), but they may acquire α-helical structure upon drying. In the model plant Arabidopsis thaliana, the LEA proteins COR15A and COR15B are highly induced upon cold treatment and are necessary for the plants to attain full freezing tolerance. Freezing leads to increased intracellular crowding due to dehydration by extracellular ice crystals...
January 21, 2017: FEBS Journal
https://www.readbyqxmd.com/read/28106390/tubulin-binding-and-polymerization-promoting-properties-of-tubulin-polymerization-promoting-proteins-are-evolutionarily-conserved
#16
Judit Oláh, Tibor Szénási, Adél Szabó, Kinga Kovács, Péter Lőw, Mauro Štifanić, Ferenc Orosz
Tubulin polymerization promoting proteins (TPPPs) constitute a eukaryotic protein family. There are three TPPP paralogs in the human genome, denoted as TPPP1-TPPP3. TPPP1 and TPPP3 are intrinsically unstructured proteins (IUPs) that bind and polymerize tubulin and stabilize microtubules, but TPPP2 does not. Vertebrate TPPPs originated from the ancient invertebrate TPPP by two-round whole-genome duplication; thus, whether the tubulin/microtubule binding function of TPPP1 and TPPP3 is a newly acquired property or was present in the invertebrate orthologs (generally one TPPP per species) has been an open question...
February 6, 2017: Biochemistry
https://www.readbyqxmd.com/read/28104810/the-foxp2-forkhead-domain-binds-to-a-variety-of-dna-sequences-with-different-rates-and-affinities
#17
Helen Webb, Olga Steeb, Ashleigh Blane, Lia Rotherham, Shaun Aron, Phillip Machanick, Heini Dirr, Sylvia Fanucchi
FOXP2 is a member of the P subfamily of FOX transcription factors, the DNA binding domain of which is the winged helix forkhead domain. In this work we show that the FOXP2 forkhead domain is able to bind to various DNA sequences, including a novel sequence identified in this work, with different affinities and rates as detected using surface plasmon resonance. Combining the experimental work with molecular docking, we show that high affinity sequences remain bound to the protein for longer, form a greater number of interactions with the protein and induce a greater structural change in the protein than low affinity sequences...
January 18, 2017: Journal of Biochemistry
https://www.readbyqxmd.com/read/28102071/temperature-induced-misfolding-in-prion-protein-evidence-of-multiple-partially-disordered-states-stabilized-by-non-native-hydrogen-bonds
#18
Neharika G Chamachi, Suman Chakrabarty
The structural basis of pathways of misfolding of a cellular prion (PrP(C)) into the toxic scrapie form (PrP(SC)) and identification of possible intermediates (e.g., PrP*) still eludes us. In this work, we have used a cumulative ∼65 μs of replica exchange molecular dynamics simulation data to construct the conformational free energy landscapes and capture the structural and thermodynamic characteristics associated with various stages of the thermal denaturation process in human prion protein. The temperature-dependent free energy surfaces consist of multiple metastable states stabilized by non-native contacts and hydrogen bonds, thus rendering the protein prone to misfolding...
February 2, 2017: Biochemistry
https://www.readbyqxmd.com/read/28096372/helical-structure-stability-and-dynamics-in-human-apolipoprotein-e3-and-e4-by-hydrogen-exchange-and-mass-spectrometry
#19
Palaniappan S Chetty, Leland Mayne, Sissel Lund-Katz, S Walter Englander, Michael C Phillips
Apolipoprotein E (apoE) plays a critical role in cholesterol transport in both peripheral circulation and brain. Human apoE is a polymorphic 299-residue protein in which the less common E4 isoform differs from the major E3 isoform only by a C112R substitution. ApoE4 interacts with lipoprotein particles and with the amyloid-β peptide, and it is associated with increased incidence of cardiovascular and Alzheimer's disease. To understand the structural basis for the differences between apoE3 and E4 functionality, we used hydrogen-deuterium exchange coupled with a fragment separation method and mass spectrometric analysis to compare their secondary structures at near amino acid resolution...
January 31, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28092832/sampling-conformational-space-of-intrinsically-disordered-proteins-in-explicit-solvent-comparison-between-well-tempered-ensemble-approach-and-solute-tempering-method
#20
Mengzhi Han, Ji Xu, Ying Ren
Intrinsically disordered proteins (IDPs) are a class of proteins that expected to be largely unstructured under physiological conditions. Due to their heterogeneous nature, experimental characterization of IDP is challenging. Temperature replica exchange molecular dynamics (T-REMD) is a widely used enhanced sampling method to probe structural characteristics of these proteins. However, its application has been hindered due to its tremendous computational cost, especially when simulating large systems in explicit solvent...
December 28, 2016: Journal of Molecular Graphics & Modelling
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