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- Volume 24, Issue 4, 2017
Protein and Peptide Letters - Volume 24, Issue 4, 2017
Volume 24, Issue 4, 2017
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Intrinsically Disordered Domains, Amyloids and Protein Liquid Phases: Evolving Concepts and Open Questions
Authors: Miguel Mompean and Douglas V. LaurentsEnzymes and structural proteins dominated thinking about protein structure and function for most of the twentieth century. In recent decades, however, we have begun to appreciate the significant physiological and pathological roles of nonglobular proteins. Amyloids first gained infamy from their implications in a score of human mortal diseases. However, they have recently been discovered to play vital physiological roles, such as memory consolidation in humans. This raises an important question: Can we inhibit pathological amyloids without affecting functional amyloids? Intrinsically disordered proteins (IDPs), many of which are prone to form amyloids, perform many essential functions, yet their importance has only been recognized in the last quarter century. A subclass of IDPs can form, under certain conditions, water immiscible liquid phases which serve to process, regulate, store or transport RNA. Perturbation of these remarkable liquid phases can lead to aggregates, such as those formed by the proteins TDP-43 and FUS, which are linked to ALS and other dementia. Here, we summarize our changing view of intrinsically disordered, liquid phase forming and amyloidogenic proteins and the uncertainties that will drive future research.
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Transforming Cytosolic Proteins into “Insoluble” and Membrane-toxic Forms Triggering Diseases/Aging by Genetic, Pathological or Environmental Factors
More LessAn increasing spectrum of diseases more than neurodegenerative diseases is characteristic of aggregation of specific proteins, while aggregation of a large number of non-specific proteins are associated with aging down to Escherichia coli. Triggered by disease-causing mutations and agingassociated damages, many well-folded cytosolic proteins become “completely insoluble” in vivo. As facilitated by our discovery in 2005 that “completely insoluble” proteins could be solubilized in unsalted water, we have deciphered that disease- and aging-associated factors act to eliminate the native folds of human VAPB-MSP and SOD1, as well as E. coli S1 ribosomal protein, consequently unlocking amphiphilic/hydrophobic regions universally existing in proteins. These disordered states with hydrophobic patches unavoidably exposed are only soluble in unsalted water but become “insoluble” in vivo with high salt concentrations. Most unexpectedly, we decoded that these disordered states acquire novel capacity to interact with membranes energetically driven by forming helices in membrane environments. Remarkably, the abnormal insertion of SOD1 mutants into ER membrane has been functionally established to trigger ER stress, an initial event of a cascade of cell specific damages in ALS pathogenesis. Together with previous results that all aggregation-prone proteins causing diseases contain “intrinsic” membrane-interacting regions, our results with “acquired” membrane- interacting capacity suggest that abnormal interactions with membranes represent a common mechanism for aggregation-prone proteins to trigger diseases and aging. Proteins, the most important functional players for all forms of life, can transform into membrane-toxic forms, if their hydrophobic/ amphiphilic regions are unlocked by genetic, pathological, or/and environmental factors, which is characteristic of aggregation.
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A Structural View of αB-crystallin Assembly and Amyloid Aggregation
Authors: Zhenying Liu, Shengnan Zhang, Dan Li and Cong LiuThe major len protein α B-crystallin (α B) is an intracellular chaperone. It belongs to the family of small heat shock proteins (sHsps) which plays a critical role in maintaining protein homeostasis and preventing protein aggregation, especially under stress conditions. Dysfunction of α B is closely related to cataract, and many neurodegenerative diseases including Alzheimer’s, Parkinson’s, and Creutzfeldt-Jakob disease. Due to the extremely heterogeneous and polydispersed nature of αB, it remains unclear how α B self-assemblies and prevents its client proteins from aggregation. In this minireview, we summarize the structural studies of αB in self-assembly, chaperoning client proteins and amyloid aggregation. We also mention the recent progress in identification of small molecules preventing αB aggregation for potential cataract treatment. This review highlights the polymorphic structures of αB under different conditions and its wide-spectrum chaperone activities, and sheds light on understanding the complex relationship among α B, client proteins and the related diseases.
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Solid-State Structure of Abeta (Aβ) in Alzheimer's Disease
Authors: Jun-Xia Lu, Xing-Qi Dong and Jian-Jun ZhangAlzheimer’s disease (AD) has become the most common neurodegenerative disease. The deposition of amyloid fibrils in the brain is one of the characteristics of AD. The fibrils are composed of amyloid-β peptide (Aβ). Aβ is produced through a series event of protease cleavage of a transmembrane protein called β-amyloid precursor protein (APP) which is commonly expressed in the brain. The production of Aβ and its propensity to aggregation to form oligomers and fibrils are believed to initiate a sequence of events that lead to AD dementia. The production of Aβ is influenced by the transmembrane domain (TM) structure of APP. The structure variety of different Aβ assemblies including oligomers and fibrils may result in different neurotoxicity to the brain. Therefore, enormous work has been carried out to study the structure of APP TM and various Aβ assemblies. Solid-state NMR has advantages in studying immobile protein structures with large molecular weight. In this review, solid-state NMR structure of APP TM and different Aβ assemblies will be discussed, especially various Aβ amyloid fibril structures. This structural information greatly enhanced our understanding in AD, providing fundamental knowledge that will help in finding a treatment for AD.
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Emerging Methods for Structural Analysis of Protein Aggregation
Authors: Eshan Khan, Subodh K. Mishra and Amit KumarProtein misfolding and aggregation is a key attribute of different neurodegenerative diseases. Misfolded and aggregated proteins are intrinsically disordered and rule out structure based drug design. The comprehensive characterization of misfolded proteins and associated aggregation pathway is prerequisite to develop therapeutics for neurodegenerative diseases caused due to the protein aggregation. Visible protein aggregates used to be the final stage during aggregation mechanism. The structural analysis of intermediate steps in such protein aggregates will help us to discern the conformational role and subsequently involved pathways. The structural analysis of protein aggregation using various biophysical methods may aid for improved therapeutics for protein misfolding and aggregation related neurodegenerative diseases. In this mini review, we have summarized different spectroscopic methods such as fluorescence spectroscopy, circular dichroism (CD), nuclear magnetic resonance (NMR) spectroscopy, Fourier transform infrared spectroscopy (FTIR), and Raman spectroscopy for structural analysis of protein aggregation. We believe that the understanding of invisible intermediate of misfolded proteins and the key steps involved during protein aggregation mechanisms may advance the therapeutic approaches for targeting neurological diseases that are caused due to misfolded proteins.
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Functional Peptides from Laminin-1 Improve the Cell Adhesion Capacity of Recombinant Mussel Adhesive Protein
Authors: Kai Wang, Lina Ji and Zichun HuaSince cell adhesion is important for cell processes such as migration and proliferation, it is a crucial consideration in biomaterial design and development. Based on the fusion of mussel adhesive protein fp151 with laminin-1-originated functional peptides we designed fusion proteins (fLA4, fLG6 and fAG73) and explored their cell adhesion properties. In our study, cell adhesion analysis showed that protein fLG6 and fLA4 had a significantly higher cell adhesion property for A549 than fp151. Moreover, protein fAG73 also displayed a strong adhesion capacity for Hela cells. In conclusion, the incorporation of functional peptides with integrin and heparin/heparan sulphate binding capacity into mussel adhesive protein will promote the application of mussel adhesive protein as cell adhesion biomaterial.
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Inhibition of p53 Mutant Peptide Aggregation In Vitro by Cationic Osmolyte Acetylcholine Chloride
Authors: Zhaolin Chen and Mathumai KanapathipillaiMutations of tumor suppressor protein p53 are present in almost about 50% of all cancers. It has been reported that the p53 mutations cause aggregation and subsequent loss of p53 function, leading to cancer progression. Here in this study we focus on the inhibitory effects of cationic osmolyte molecules acetylcholine chloride, and choline on an aggregation prone 10 amino acid p53 mutant peptide WRPILTIITL, and the corresponding wildtype peptide RRPILTIITL in vitro. The characterization tools used for this study include Thioflavin- T (ThT) induced fluorescence, transmission electron microscopy (TEM), congo red binding, turbidity, dynamic light scattering (DLS), and cell viability assays. The results show that acetylcholine chloride in micromolar concentrations significantly inhibit p53 mutant peptide aggregation in vitro, and could be promising candidate for p53 mutant/ misfolded protein aggregation inhibition.
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Cold Shock Protein A from Corynebacterium pseudotuberculosis: Role of Electrostatic Forces in the Stability of the Secondary Structure
The conformational stability of the Cold shock protein A (CspA) from C. pseudotuberculosis (Cp), a nucleic acid binding protein in function of pH and salt concentration was examined by using differential scanning calorimetry and CD spectroscopy in combination with computational analysis to identify the specify amino acids undergoing change. Our approach identified a sodiumbinding site in CpCspA and at pH 8.0 a significant reduction in the β-sheet content was observed which resulted in a decrease of the protein thermal stability. The computational analyses identified His30 and His65 as the amino acids with the largest charge shifts at different pHs. His30/His65 are part of the extensive hydrogen bonding network and along with the ion-binding site are essential for the conformational stability of CspA.
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Purification and Characterization of 2S Albumin from Seeds of Wrightia tinctoria Exhibiting Antibacterial and DNase Activity
2S albumin is a low-molecular-weight seed storage protein belonging to the prolamin superfamily. In the present work a small 2S albumin (WTA) protein of ~16 kDa has been purified from the seeds of Wrightia tinctoria. The WTA is a heterodimer protein with a small subunit of ~5 kDa and a larger subunit of ~11 kDa bridged together through disulphide bonds. The protein exhibits deoxyribonucleases activity against closed circular pBR322 plasmid DNA and linear BL21 genomic DNA. The protein also showed antibacterial activity against Morexalla catarrhalis. CD studies indicate a high α-helical content in the protein. The conserved disulphide bonds in the protein suggest that the WTA is highly stable under high pH and temperature like other 2S albumin.
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Volumes & issues
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Volume 31 (2024)
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Volume 30 (2023)
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Volume 29 (2022)
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Volume 28 (2021)
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Volume 27 (2020)
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Volume 26 (2019)
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Volume 25 (2018)
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Volume 24 (2017)
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Volume 23 (2016)
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Volume 22 (2015)
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Volume 21 (2014)
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Volume 20 (2013)
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Volume 19 (2012)
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Volume 18 (2011)
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Volume 17 (2010)
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Volume 16 (2009)
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Volume 15 (2008)
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Volume 14 (2007)
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Volume 13 (2006)
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Volume 12 (2005)
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Volume 11 (2004)
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Volume 10 (2003)
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Volume 9 (2002)
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Volume 8 (2001)