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Protein unfolding and translocation

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https://www.readbyqxmd.com/read/28624220/tat-hafgf14-154-upregulates-adam10-to-attenuate-the-alzheimer-phenotype-of-app-ps1-mice-through-the-pi3k-creb-ire1%C3%AE-xbp1-pathway
#1
Tian Meng, Qin Cao, Peng Lei, Ashley I Bush, Qi Xiang, Zhijian Su, Xiang He, Jack T Rogers, Ing-Ming Chiu, Qihao Zhang, Yadong Huang
Acid fibroblast growth factor (aFGF) has shown neuroprotection in Alzheimer's disease (AD) models in previous studies, yet its mechanism is still uncertain. Here we report that the efficacy of Tat-haFGF14-154 is markedly increased when loaded cationic liposomes for intranasal delivery are intranasally administered to APP/PS1 mice. Our results demonstrated that liposomal Tat-haFGF14-154 treatment significantly ameliorated behavioral deficits, relieved brain Aβ burden, and increased the expression and activity of disintegrin and metalloproteinase domain-containing protein 10 (ADAM10) in the brain...
June 16, 2017: Molecular Therapy. Nucleic Acids
https://www.readbyqxmd.com/read/28619716/ratchet-like-polypeptide-translocation-mechanism-of-the-aaa-disaggregase-hsp104
#2
Stephanie N Gates, Adam L Yokom, JiaBei Lin, Meredith E Jackrel, Alexandrea N Rizo, Nathan M Kendsersky, Courtney E Buell, Elizabeth A Sweeny, Korrie L Mack, Edward Chuang, Mariana P Torrente, Min Su, James Shorter, Daniel R Southworth
Hsp100 polypeptide translocases are conserved AAA+ machines that maintain proteostasis by unfolding aberrant and toxic proteins for refolding or proteolytic degradation. The Hsp104 disaggregase from S. cerevisiae solubilizes stress-induced amorphous aggregates and amyloid. The structural basis for substrate recognition and translocation is unknown. Using a model substrate (casein), we report cryo-EM structures at near-atomic resolution of Hsp104 in different translocation states. Substrate interactions are mediated by conserved, pore-loop tyrosines that contact an 80 Å-long unfolded polypeptide along the axial channel...
June 15, 2017: Science
https://www.readbyqxmd.com/read/28583440/proteasome-structure-and-assembly
#3
REVIEW
Lauren Budenholzer, Chin Leng Cheng, Yanjie Li, Mark Hochstrasser
The eukaryotic 26S proteasome is a large multi-subunit complex that degrades the majority of proteins in the cell under normal conditions. The 26S proteasome can be divided into two subcomplexes: the 19S regulatory particle (RP) and the 20S core particle (CP). Most substrates are first covalently modified by ubiquitin, which then directs them to the proteasome. The function of the RP is to recognize, unfold, deubiquitylate and translocate substrates into the CP, which contains the proteolytic sites of the proteasome...
June 2, 2017: Journal of Molecular Biology
https://www.readbyqxmd.com/read/28559891/systematic-optimization-of-protein-secretory-pathways-in-saccharomyces-cerevisiae-to-increase-expression-of-hepatitis-b-small-antigen
#4
Jiayuan Sheng, Hunter Flick, Xueyang Feng
Hepatitis B is a major disease that chronically infects millions of people in the world, especially in developing countries. Currently, one of the effective vaccines to prevent Hepatitis B is the Hepatitis B Small Antigen (HBsAg), which is mainly produced by the recombinant yeast Saccharomyces cerevisiae. In order to bring down the price, which is still too high for people in developing countries to afford, it is important to understand key cellular processes that limit protein expression. In this study, we took advantage of yeast knockout collection (YKO) and screened 194 S...
2017: Frontiers in Microbiology
https://www.readbyqxmd.com/read/28548229/endoplasmic-reticulum-stress-in-the-heart-the-insights-into-mechanisms-and-drug-targets
#5
REVIEW
Shunyao Wang, Pablo Binder, Qiru Fang, Zhenzhong Wang, Wei Xiao, Wei Liu, Xin Wang
The endoplasmic reticulum (ER) serves several essential cellular functions including protein synthesis, protein folding, protein translocation, calcium homoeostasis and lipid biosynthesis. Physiological or pathological stimuli which disrupt ER homoeostasis and disturb its functions lead to an accumulation of misfolded and unfolded proteins, a condition referred to as ER stress. ER stress triggers unfolded protein response (UPR) to restore the homoeostasis of ER through activating transcriptional and translational pathways...
May 26, 2017: British Journal of Pharmacology
https://www.readbyqxmd.com/read/28475898/molecular-mechanism-of-substrate-processing-by-the-cdc48-atpase-complex
#6
Nicholas O Bodnar, Tom A Rapoport
The Cdc48 ATPase and its cofactors Ufd1/Npl4 (UN) extract polyubiquitinated proteins from membranes or macromolecular complexes, but how they perform these functions is unclear. Cdc48 consists of an N-terminal domain that binds UN and two stacked hexameric ATPase rings (D1 and D2) surrounding a central pore. Here, we use purified components to elucidate how the Cdc48 complex processes substrates. After interaction of the polyubiquitin chain with UN, ATP hydrolysis by the D2 ring moves the polypeptide completely through the double ring, generating a pulling force on the substrate and causing its unfolding...
May 4, 2017: Cell
https://www.readbyqxmd.com/read/28433661/differential-protein-acetylation-assists-import-of-excess-sod2-into-mitochondria-and-mediates-sod2-aggregation-associated-with-cardiac-hypertrophy-in-the-murine-sod2-tg-heart
#7
Liwen Zhang, Chwen-Lih Chen, Patrick T Kang, Zhicheng Jin, Yeong-Renn Chen
SOD2 is the primary antioxidant enzyme neutralizing (•)O2(-) in mitochondria. Cardiac-specific SOD2 overexpression (SOD2-tg) induces supernormal function and cardiac hypertrophy in the mouse heart. However, the reductive stress imposed by SOD2 overexpression results in protein aggregation of SOD2 pentamers and differential hyperacetylation of SOD2 in the mitochondria and cytosol. Here, we studied SOD2 acetylation in SOD2-tg and wild-type mouse hearts. LC-MS/MS analysis indicated the presence of four acetylated lysines in matrix SOD2 and nine acetylated lysines in cytosolic SOD2 from the SOD2-tg heart...
April 20, 2017: Free Radical Biology & Medicine
https://www.readbyqxmd.com/read/28421184/the-proteasomal-atpases-use-a-slow-but-highly-processive-strategy-to-unfold-proteins
#8
Aaron Snoberger, Raymond T Anderson, David M Smith
All domains of life have ATP-dependent compartmentalized proteases that sequester their peptidase sites on their interior. ATPase complexes will often associate with these compartmentalized proteases in order to unfold and inject substrates into the protease for degradation. Significant effort has been put into understanding how ATP hydrolysis is used to apply force to proteins and cause them to unfold. The unfolding kinetics of the bacterial ATPase, ClpX, have been shown to resemble a fast motor that traps unfolded intermediates as a strategy to unfold proteins...
2017: Frontiers in Molecular Biosciences
https://www.readbyqxmd.com/read/28419599/mycobacterium-tuberculosis-proteasomal-atpase-mpa-has-a-%C3%AE-grasp-domain-that-hinders-docking-with-the-proteasome-core-protease
#9
Yujie Wu, Kuan Hu, Defeng Li, Lin Bai, Shaoqing Yang, Jordan B Jastrab, Shuhao Xiao, Yonglin Hu, Susan Zhang, K Heran Darwin, Tao Wang, Huilin Li
Mycobacterium tuberculosis (Mtb) has a proteasome system that is essential for its ability to cause lethal infections in mice. A key component of the system is the proteasomal adenosine triphosphatase (ATPase) Mpa, which captures, unfolds, and translocates protein substrates into the Mtb proteasome core particle for degradation. Here, we report the crystal structures of near full-length hexameric Mtb Mpa in apo and ADP-bound forms. Surprisingly, the structures revealed a ubiquitin-like β-grasp domain that precedes the proteasome-activating carboxyl terminus...
April 17, 2017: Molecular Microbiology
https://www.readbyqxmd.com/read/28417122/frequency-control-of-protein-translocation-across-an-oscillating-nanopore
#10
Fabio Cecconi, Muhammad Adnan Shahzad, Umberto Marini Bettolo Marconi, Angelo Vulpiani
The translocation of a lipid binding protein (LBP) is studied using a phenomenological coarse-grained computational model that simplifies both chain and pore geometry. We investigated via molecular dynamics the interplay between transport and unfolding in the presence of a nanopore whose section oscillates periodically in time with a frequency ω, a motion often referred to as the radial breathing mode (RBM). We found that the LPB when mechanically pulled into the vibrating nanopore exhibits a translocation dynamics that in some frequency range is accelerated and shows a frequency locking to the pore dynamics...
April 18, 2017: Physical Chemistry Chemical Physics: PCCP
https://www.readbyqxmd.com/read/28407373/activation-of-the-arabidopsis-membrane-bound-transcription-factor-bzip28-is-mediated-by-site-2-protease-but-not-site-1-protease
#11
Yuji Iwata, Makoto Ashida, Chisa Hasegawa, Kazuki Tabara, Kei-Ichiro Mishiba, Nozomu Koizumi
The unfolded protein response (UPR) is a homeostatic cellular response conserved in eukaryotic cells to alleviate the accumulation of unfolded proteins in the endoplasmic reticulum (ER). Arabidopsis bZIP28 is a membrane-bound transcription factor activated by proteolytic cleavage in response to ER stress, thereby releasing its cytosolic portion containing the bZIP domain from the membrane to translocate into the nucleus where it induces the transcription of genes encoding ER-resident molecular chaperones and folding enzymes...
April 13, 2017: Plant Journal: for Cell and Molecular Biology
https://www.readbyqxmd.com/read/28397859/an-optimized-transit-peptide-for-effective-targeting-of-diverse-foreign-proteins-into-chloroplasts-in-rice
#12
Bo-Ran Shen, Cheng-Hua Zhu, Zhen Yao, Li-Li Cui, Jian-Jun Zhang, Cheng-Wei Yang, Zheng-Hui He, Xin-Xiang Peng
Various chloroplast transit peptides (CTP) have been used to successfully target some foreign proteins into chloroplasts, but for other proteins these same CTPs have reduced localization efficiencies or fail completely. The underlying cause of the failures remains an open question, and more effective CTPs are needed. In this study, we initially observed that two E.coli enzymes, EcTSR and EcGCL, failed to be targeted into rice chloroplasts by the commonly-used rice rbcS transit peptide (rCTP) and were subsequently degraded...
April 11, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28389941/fuel-of-the-bacterial-flagellar-type-iii-protein-export-apparatus
#13
Tohru Minamino, Miki Kinoshita, Keiichi Namba
The flagellar type III export apparatus utilizes ATP and proton motive force (PMF) across the cytoplasmic membrane as the energy sources and transports flagellar component proteins from the cytoplasm to the distal growing end of the growing structure to construct the bacterial flagellum beyond the cellular membranes. The flagellar type III export apparatus coordinates flagellar protein export with assembly by ordered export of substrates to parallel with their order of the assembly. The export apparatus is composed of a PMF-driven transmembrane export gate complex and a cytoplasmic ATPase complex...
2017: Methods in Molecular Biology
https://www.readbyqxmd.com/read/28286085/hspa5-gene-encoding-hsp70-chaperone-bip-in-the-endoplasmic-reticulum
#14
REVIEW
Jie Wang, Jessica Lee, David Liem, Peipei Ping
The HSPA5 gene encodes the binding immunoglobulin protein (BiP), an Hsp70 family chaperone localized in the ER lumen. As a highly conserved molecular chaperone, BiP assists in a wide range of folding processes via its two structural domains, a nucleotide-binding domain (NBD) and substrate-binding domain (SBD). BiP is also an essential component of the translocation machinery for protein import into the ER, a regulator for Ca(2+) homeostasis in the ER, as well as a facilitator of ER-associated protein degradation (ERAD) via retrograde transportation of aberrant proteins across the ER membrane...
June 30, 2017: Gene
https://www.readbyqxmd.com/read/28237106/methods-to-study-chaperone-mediated-autophagy
#15
E Arias
Chaperone-mediated autophagy (CMA), a selective form of degradation of cytosolic proteins in lysosomes, contributes to maintenance of proteostasis and to the cellular adaptation to stress. CMA substrates are selectively recognized and delivered by a cytosolic chaperone to the lysosomal surface, where, upon unfolding, they are internalized through a membrane translocation complex. Defective or dysfunctional CMA has been associated with human pathologies such as neurodegeneration, cancer, immunodeficiency, or diabetes, increasing the overall interest in methods to monitor this selective autophagic pathway...
2017: Methods in Enzymology
https://www.readbyqxmd.com/read/28223361/covalently-linked-hslu-hexamers-support-a-probabilistic-mechanism-that-links-atp-hydrolysis-to-protein-unfolding-and-translocation
#16
Vladimir Baytshtok, Jiejin Chen, Steven E Glynn, Andrew R Nager, Robert A Grant, Tania A Baker, Robert T Sauer
The HslUV proteolytic machine consists of HslV, a double-ring self-compartmentalized peptidase, and one or two AAA+ HslU ring hexamers that hydrolyze ATP to power the unfolding of protein substrates and their translocation into the proteolytic chamber of HslV. Here, we use genetic tethering and disulfide bonding strategies to construct HslU pseudohexamers containing mixtures of ATPase active and inactive subunits at defined positions in the hexameric ring. Genetic tethering impairs HslV binding and degradation, even for pseudohexamers with six active subunits, but disulfide-linked pseudohexamers do not have these defects, indicating that the peptide tether interferes with HslV interactions...
April 7, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28216041/structure-of-a-type-1-secretion-system-abc-transporter
#17
Jacob L W Morgan, Justin F Acheson, Jochen Zimmer
Type-1 secretion systems (T1SSs) represent a widespread mode of protein secretion across the cell envelope in Gram-negative bacteria. The T1SS is composed of an inner-membrane ABC transporter, a periplasmic membrane-fusion protein, and an outer-membrane porin. These three components assemble into a complex spanning both membranes and providing a conduit for the translocation of unfolded polypeptides. We show that ATP hydrolysis and assembly of the entire T1SS complex is necessary for protein secretion. Furthermore, we present a 3...
March 7, 2017: Structure
https://www.readbyqxmd.com/read/28115689/structural-insights-into-the-functional-cycle-of-the-atpase-module-of-the-26s-proteasome
#18
Marc Wehmer, Till Rudack, Florian Beck, Antje Aufderheide, Günter Pfeifer, Jürgen M Plitzko, Friedrich Förster, Klaus Schulten, Wolfgang Baumeister, Eri Sakata
In eukaryotic cells, the ubiquitin-proteasome system (UPS) is responsible for the regulated degradation of intracellular proteins. The 26S holocomplex comprises the core particle (CP), where proteolysis takes place, and one or two regulatory particles (RPs). The base of the RP is formed by a heterohexameric AAA(+) ATPase module, which unfolds and translocates substrates into the CP. Applying single-particle cryo-electron microscopy (cryo-EM) and image classification to samples in the presence of different nucleotides and nucleotide analogs, we were able to observe four distinct conformational states (s1 to s4)...
February 7, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28115202/secondary-structure-preferences-of-the-anthrax-toxin-protective-antigen-translocase
#19
Debasis Das, Bryan A Krantz
In order for many proteins to move across hydrophobic membrane bilayers, they must be unfolded and translocated by a membrane-embedded channel. These translocase channels interact with the substrate proteins they translocate via hydrophobic pore loops and cleft structures called clamps. The molecular basis for how clamps facilitate unfolding and translocation is poorly understood. Anthrax toxin is composed of three proteins, a translocase channel-forming subunit, called protective antigen (PA), and two substrate proteins, called lethal factor (LF) and edema factor...
March 10, 2017: Journal of Molecular Biology
https://www.readbyqxmd.com/read/28069863/ubiquitin-recognition-by-the-proteasome
#20
REVIEW
Yasushi Saeki
The 26S proteasome is a 2.5-MDa complex responsible for the selective, ATP-dependent degradation of ubiquitylated proteins in eukaryotic cells. Substrates in hundreds cellular pathways are timely ubiquitylated and converged to the proteasome by direct recognition or by multiple shuttle factors. Engagement of substrate protein triggers conformational changes of the proteasome, which drive substrate unfolding, deubiquitylation and translocation of substrates to proteolytic sites. Recent studies have challenged the previous paradigm that Lys48-linked tetraubiquitin is a minimal degradation signal: in addition, monoubiquitylation or multiple short ubiquitylations can serve as the targeting signal for proteasomal degradation...
February 1, 2017: Journal of Biochemistry
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