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4 results on '"polyglutamine peptides"'

1. Binding structures of SERF1a with NT17-polyQ peptides of huntingtin exon 1 revealed by SEC-SWAXS, NMR and molecular simulation

Author

Tien-Chang Lin, Orion Shih, Tien-Ying Tsai, Yi-Qi Yeh, Kuei-Fen Liao, Bradley W. Mansel, Ying-Jen Shiu, Chi-Fon Chang, An-Chung Su, Yun-Ru Chen, and U-Ser Jeng

Subjects
huntingtin exon 1, polyglutamine peptides, serf1a, sec-swaxs, nmr, molecular simulation, huntington's disease, Crystallography, QD901-999
Abstract

The aberrant fibrillization of huntingtin exon 1 (Httex1) characterized by an expanded polyglutamine (polyQ) tract is a defining feature of Huntington's disease, a neurodegenerative disorder. Recent investigations underscore the involvement of a small EDRK-rich factor 1a (SERF1a) in promoting Httex1 fibrillization through interactions with its N terminus. By establishing an integrated approach with size-exclusion-column-based small- and wide-angle X-ray scattering (SEC-SWAXS), NMR, and molecular simulations using Rosetta, the analysis here reveals a tight binding of two NT17 fragments of Httex1 (comprising the initial 17 amino acids at the N terminus) to the N-terminal region of SERF1a. In contrast, examination of the complex structure of SERF1a with a coiled NT17-polyQ peptide (33 amino acids in total) indicates sparse contacts of the NT17 and polyQ segments with the N-terminal side of SERF1a. Furthermore, the integrated SEC-SWAXS and molecular-simulation analysis suggests that the coiled NT17 segment can transform into a helical conformation when associated with a polyQ segment exhibiting high helical content. Intriguingly, NT17-polyQ peptides with enhanced secondary structures display diminished interactions with SERF1a. This insight into the conformation-dependent binding of NT17 provides clues to a catalytic association mechanism underlying SERF1a's facilitation of Httext1 fibrillization.

Published
2024
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2. Binding structures of SERF1a with NT17-polyQ peptides of huntingtin exon 1 revealed by SEC-SWAXS, NMR and molecular simulation.

Author

Lin TC, Shih O, Tsai TY, Yeh YQ, Liao KF, Mansel BW, Shiu YJ, Chang CF, Su AC, Chen YR, and Jeng US

Subjects
Humans, Exons genetics, Protein Binding, Huntington Disease genetics, Huntington Disease metabolism, Molecular Dynamics Simulation, Magnetic Resonance Spectroscopy, X-Ray Diffraction, Huntingtin Protein genetics, Huntingtin Protein chemistry, Huntingtin Protein metabolism, Peptides chemistry, Peptides metabolism, Peptides genetics
Abstract

The aberrant fibrillization of huntingtin exon 1 (Httex1) characterized by an expanded polyglutamine (polyQ) tract is a defining feature of Huntington's disease, a neurodegenerative disorder. Recent investigations underscore the involvement of a small EDRK-rich factor 1a (SERF1a) in promoting Httex1 fibrillization through interactions with its N terminus. By establishing an integrated approach with size-exclusion-column-based small- and wide-angle X-ray scattering (SEC-SWAXS), NMR, and molecular simulations using Rosetta, the analysis here reveals a tight binding of two NT17 fragments of Httex1 (comprising the initial 17 amino acids at the N terminus) to the N-terminal region of SERF1a. In contrast, examination of the complex structure of SERF1a with a coiled NT17-polyQ peptide (33 amino acids in total) indicates sparse contacts of the NT17 and polyQ segments with the N-terminal side of SERF1a. Furthermore, the integrated SEC-SWAXS and molecular-simulation analysis suggests that the coiled NT17 segment can transform into a helical conformation when associated with a polyQ segment exhibiting high helical content. Intriguingly, NT17-polyQ peptides with enhanced secondary structures display diminished interactions with SERF1a. This insight into the conformation-dependent binding of NT17 provides clues to a catalytic association mechanism underlying SERF1a's facilitation of Httext1 fibrillization., (open access.)

Published
2024
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3. Versatile members of the DNAJ family show Hsp70 dependent anti-aggregation activity on RING1 mutant parkin C289G

Author

Kakkar, Vaishali, Kuiper, E F Elsiena, Pandey, Abhinav, Braakman, Ineke, Kampinga, Harm H, Sub Cellular Protein Chemistry, Cellular Protein Chemistry, Molecular Neuroscience and Ageing Research (MOLAR), Sub Cellular Protein Chemistry, and Cellular Protein Chemistry

Subjects
0301 basic medicine, Ubiquitin-Protein Ligases, Protein domain, Mutant, Nerve Tissue Proteins, Protein aggregation, Biology, DNAJ Protein, medicine.disease_cause, Article, Parkin, DISEASE, UBIQUITIN, 03 medical and health sciences, 0302 clinical medicine, Protein Domains, Ubiquitin, Chaperones, medicine, Humans, HSP70 Heat-Shock Proteins, Genetics, POLYGLUTAMINE PEPTIDES, Mutation, Multidisciplinary, MUTATIONS, HEK 293 cells, Parkinson Disease, HSP40 Heat-Shock Proteins, ALPHA-SYNUCLEIN AGGREGATION, DISTINCT FUNCTIONS, HEK293 Cells, 030104 developmental biology, Amino Acid Substitution, MOLECULAR CHAPERONES, AMYLOID FORMATION, Proteolysis, CELLS, biology.protein, 030217 neurology & neurosurgery
Abstract

Parkinson’s disease is one of the most common neurodegenerative disorders and several mutations in different genes have been identified to contribute to the disease. A loss of function parkin RING1 domain mutant (C289G) is associated with autosomal-recessive juvenile-onset Parkinsonism (AR-JP) and displays altered solubility and sequesters into aggregates. Single overexpression of almost each individual member of the Hsp40 (DNAJ) family of chaperones efficiently reduces parkin C289G aggregation and requires interaction with and activity of endogenously expressed Hsp70 s. For DNAJB6 and DNAJB8, potent suppressors of aggregation of polyglutamine proteins for which they rely mainly on an S/T-rich region, it was found that the S/T-rich region was dispensable for suppression of parkin C289G aggregation. Our data implies that different disease-causing proteins pose different challenges to the protein homeostasis system and that DNAJB6 and DNAJB8 are highly versatile members of the DNAJ protein family with multiple partially non-overlapping modes of action with respect to handling disease-causing proteins, making them interesting potential therapeutic targets.

Published
2016

4. Interaction of the molecular chaperone DNAJB6 with growing amyloid-beta 42 (Aβ42) aggregates leads to sub-stoichiometric inhibition of amyloid formation

Author

Cecilia Emanuelsson, Rasha M. Hussein, Wilbert C. Boelens, Tuomas P. J. Knowles, Reem M. Hashem, Paolo Arosio, Christopher M. Dobson, Cecilia Månsson, Sara Linse, Harm H. Kampinga, and Molecular Neuroscience and Ageing Research (MOLAR)

Subjects
Circular dichroism, Protein Folding, Amyloid-beta (Aβ), Peptide, Plasma protein binding, Protein aggregation, Biochemistry, TOXICITY, chemistry.chemical_compound, OLIGOMERS, BINDING, Amyloid Fibril Formation, GeneralLiterature_REFERENCE(e.g.,dictionaries,encyclopedias,glossaries), chemistry.chemical_classification, biology, Circular Dichroism, Bio-Molecular Chemistry, Neurodegenerative Diseases, COMMON MECHANISM, ALZHEIMERS-DISEASE, Thioflavin, Protein folding, Chaperone DnaJ (DnaJ), Molecular Biophysics, Protein Binding, Amyloid, ALPHA-B-CRYSTALLIN, Nerve Tissue Proteins, Fibril, NUCLEATION MECHANISM, Alzheimer Disease, Humans, Aggregation Kinetics, Molecular Biology, Serum Albumin, Cell Proliferation, POLYGLUTAMINE PEPTIDES, Hsp40, Amyloid beta-Peptides, Neurodegenerative Disease, Inhibition Mechanism, alpha-Crystallin B Chain, Cell Biology, HSP40 Heat-Shock Proteins, Protein Aggregation, Peptide Fragments, Protein Structure, Tertiary, Kinetics, chemistry, Chaperone (protein), biology.protein, Biophysics, Molecular Chaperones
Abstract

The human molecular chaperone protein DNAJB6 was recently found to inhibit the formation of amyloid fibrils from polyglutamine peptides associated with neurodegenerative disorders such as Huntington disease. We show in the present study that DNAJB6 also inhibits amyloid formation by an even more aggregation-prone peptide (the amyloid-beta peptide, Aβ42, implicated in Alzheimer disease) in a highly efficient manner. By monitoring fibril formation using Thioflavin T fluorescence and far-UV CD spectroscopy, we have found that the aggregation of Aβ42 is retarded by DNAJB6 in a concentration-dependent manner, extending to very low sub-stoichiometric molar ratios of chaperone to peptide. Quantitative kinetic analysis and immunochemistry studies suggest that the high inhibitory efficiency is due to the interactions of the chaperone with aggregated forms of Aβ42 rather than the monomeric form of the peptide. This interaction prevents the growth of such species to longer fibrils and inhibits the formation of new amyloid fibrils through both primary and secondary nucleation. A low dissociation rate of DNAJB6 from Aβ42 aggregates leads to its incorporation into growing fibrils and hence to its gradual depletion from solution with time. When DNAJB6 is eventually depleted, fibril proliferation takes place, but the inhibitory activity can be prolonged by introducing DNAJB6 at regular intervals during the aggregation reaction. These results reveal the highly efficacious mode of action of this molecular chaperone against protein aggregation, and demonstrate that the role of molecular chaperones can involve interactions with multiple aggregated species leading to the inhibition of both principal nucleation pathways through which aggregates are able to form., Journal of Biological Chemistry, 289, ISSN:0021-9258, ISSN:1083-351X

Published
2014
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