The Impact of Hidden Structure on Aggregate Disassembly by Molecular Chaperones
Protein aggregation, or the uncontrolled self-assembly of partially folded proteins, is an ever-present danger for living organisms. Unimpeded, protein aggregation can result in severe cellular dysfunction and disease. A group of proteins known as molecular chaperones is responsible for dismantling...
| Main Authors: | , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-07-01
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| Series: | Frontiers in Molecular Biosciences |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fmolb.2022.915307/full |
| _version_ | 1828331588933386240 |
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| author | Daniel Shoup Andrew Roth Jason Puchalla Hays S. Rye |
| author_facet | Daniel Shoup Andrew Roth Jason Puchalla Hays S. Rye |
| author_sort | Daniel Shoup |
| collection | DOAJ |
| description | Protein aggregation, or the uncontrolled self-assembly of partially folded proteins, is an ever-present danger for living organisms. Unimpeded, protein aggregation can result in severe cellular dysfunction and disease. A group of proteins known as molecular chaperones is responsible for dismantling protein aggregates. However, how protein aggregates are recognized and disassembled remains poorly understood. Here we employ a single particle fluorescence technique known as Burst Analysis Spectroscopy (BAS), in combination with two structurally distinct aggregate types grown from the same starting protein, to examine the mechanism of chaperone-mediated protein disaggregation. Using the core bi-chaperone disaggregase system from Escherichia coli as a model, we demonstrate that, in contrast to prevailing models, the overall size of an aggregate particle has, at most, a minor influence on the progression of aggregate disassembly. Rather, we show that changes in internal structure, which have no observable impact on aggregate particle size or molecular chaperone binding, can dramatically limit the ability of the bi-chaperone system to take aggregates apart. In addition, these structural alterations progress with surprising speed, rendering aggregates resistant to disassembly within minutes. Thus, while protein aggregate structure is generally poorly defined and is often obscured by heterogeneous and complex particle distributions, it can have a determinative impact on the ability of cellular quality control systems to process protein aggregates. |
| first_indexed | 2024-04-13T20:54:41Z |
| format | Article |
| id | doaj.art-72eea221ff8d4178ae06b81b4e3fc02e |
| institution | Directory Open Access Journal |
| issn | 2296-889X |
| language | English |
| last_indexed | 2024-04-13T20:54:41Z |
| publishDate | 2022-07-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Molecular Biosciences |
| spelling | doaj.art-72eea221ff8d4178ae06b81b4e3fc02e2022-12-22T02:30:23ZengFrontiers Media S.A.Frontiers in Molecular Biosciences2296-889X2022-07-01910.3389/fmolb.2022.915307915307The Impact of Hidden Structure on Aggregate Disassembly by Molecular ChaperonesDaniel Shoup0Andrew Roth1Jason Puchalla2Hays S. Rye3Department of Biochemistry and Biophysics, Texas A&M University, College Station, TX, United StatesDepartment of Biochemistry and Biophysics, Texas A&M University, College Station, TX, United StatesDepartment of Physics, Princeton University, Princeton, NJ, United StatesDepartment of Biochemistry and Biophysics, Texas A&M University, College Station, TX, United StatesProtein aggregation, or the uncontrolled self-assembly of partially folded proteins, is an ever-present danger for living organisms. Unimpeded, protein aggregation can result in severe cellular dysfunction and disease. A group of proteins known as molecular chaperones is responsible for dismantling protein aggregates. However, how protein aggregates are recognized and disassembled remains poorly understood. Here we employ a single particle fluorescence technique known as Burst Analysis Spectroscopy (BAS), in combination with two structurally distinct aggregate types grown from the same starting protein, to examine the mechanism of chaperone-mediated protein disaggregation. Using the core bi-chaperone disaggregase system from Escherichia coli as a model, we demonstrate that, in contrast to prevailing models, the overall size of an aggregate particle has, at most, a minor influence on the progression of aggregate disassembly. Rather, we show that changes in internal structure, which have no observable impact on aggregate particle size or molecular chaperone binding, can dramatically limit the ability of the bi-chaperone system to take aggregates apart. In addition, these structural alterations progress with surprising speed, rendering aggregates resistant to disassembly within minutes. Thus, while protein aggregate structure is generally poorly defined and is often obscured by heterogeneous and complex particle distributions, it can have a determinative impact on the ability of cellular quality control systems to process protein aggregates.https://www.frontiersin.org/articles/10.3389/fmolb.2022.915307/fullprotein disaggregasemolecular chaperonesingle particle fluorescenceprotein aggregationprotein aggregate detection |
| spellingShingle | Daniel Shoup Andrew Roth Jason Puchalla Hays S. Rye The Impact of Hidden Structure on Aggregate Disassembly by Molecular Chaperones Frontiers in Molecular Biosciences protein disaggregase molecular chaperone single particle fluorescence protein aggregation protein aggregate detection |
| title | The Impact of Hidden Structure on Aggregate Disassembly by Molecular Chaperones |
| title_full | The Impact of Hidden Structure on Aggregate Disassembly by Molecular Chaperones |
| title_fullStr | The Impact of Hidden Structure on Aggregate Disassembly by Molecular Chaperones |
| title_full_unstemmed | The Impact of Hidden Structure on Aggregate Disassembly by Molecular Chaperones |
| title_short | The Impact of Hidden Structure on Aggregate Disassembly by Molecular Chaperones |
| title_sort | impact of hidden structure on aggregate disassembly by molecular chaperones |
| topic | protein disaggregase molecular chaperone single particle fluorescence protein aggregation protein aggregate detection |
| url | https://www.frontiersin.org/articles/10.3389/fmolb.2022.915307/full |
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