Friends in need: How chaperonins recognize and remodel proteins that require folding assistance
Chaperonins are biological nanomachines that help newly translated proteins to fold by rescuing them from kinetically trapped misfolded states. Protein folding assistance by the chaperonin machinery is obligatory in vivo for a subset of proteins in the bacterial proteome. Chaperonins are large oligo...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-11-01
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| Series: | Frontiers in Molecular Biosciences |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fmolb.2022.1071168/full |
| _version_ | 1828298583865032704 |
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| author | George Stan George H. Lorimer D. Thirumalai D. Thirumalai |
| author_facet | George Stan George H. Lorimer D. Thirumalai D. Thirumalai |
| author_sort | George Stan |
| collection | DOAJ |
| description | Chaperonins are biological nanomachines that help newly translated proteins to fold by rescuing them from kinetically trapped misfolded states. Protein folding assistance by the chaperonin machinery is obligatory in vivo for a subset of proteins in the bacterial proteome. Chaperonins are large oligomeric complexes, with unusual seven fold symmetry (group I) or eight/nine fold symmetry (group II), that form double-ring constructs, enclosing a central cavity that serves as the folding chamber. Dramatic large-scale conformational changes, that take place during ATP-driven cycles, allow chaperonins to bind misfolded proteins, encapsulate them into the expanded cavity and release them back into the cellular environment, regardless of whether they are folded or not. The theory associated with the iterative annealing mechanism, which incorporated the conformational free energy landscape description of protein folding, quantitatively explains most, if not all, the available data. Misfolded conformations are associated with low energy minima in a rugged energy landscape. Random disruptions of these low energy conformations result in higher free energy, less folded, conformations that can stochastically partition into the native state. Two distinct mechanisms of annealing action have been described. Group I chaperonins (GroEL homologues in eubacteria and endosymbiotic organelles), recognize a large number of misfolded proteins non-specifically and operate through highly coordinated cooperative motions. By contrast, the less well understood group II chaperonins (CCT in Eukarya and thermosome/TF55 in Archaea), assist a selected set of substrate proteins. Sequential conformational changes within a CCT ring are observed, perhaps promoting domain-by-domain substrate folding. Chaperonins are implicated in bacterial infection, autoimmune disease, as well as protein aggregation and degradation diseases. Understanding the chaperonin mechanism and the specific proteins they rescue during the cell cycle is important not only for the fundamental aspect of protein folding in the cellular environment, but also for effective therapeutic strategies. |
| first_indexed | 2024-04-13T12:43:28Z |
| format | Article |
| id | doaj.art-25b0066998d04a3da6d890f26958027c |
| institution | Directory Open Access Journal |
| issn | 2296-889X |
| language | English |
| last_indexed | 2024-04-13T12:43:28Z |
| publishDate | 2022-11-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Molecular Biosciences |
| spelling | doaj.art-25b0066998d04a3da6d890f26958027c2022-12-22T02:46:26ZengFrontiers Media S.A.Frontiers in Molecular Biosciences2296-889X2022-11-01910.3389/fmolb.2022.10711681071168Friends in need: How chaperonins recognize and remodel proteins that require folding assistanceGeorge Stan0George H. Lorimer1D. Thirumalai2D. Thirumalai3Department of Chemistry, University of Cincinnati, Cincinnati, OH, United StatesCenter for Biomolecular Structure and Organization, Department of Chemistry and Biochemistry, University of Maryland, College Park, MD, United StatesDepartment of Chemistry, University of Texas, Austin, TX, United StatesDepartment of Physics, University of Texas, Austin, TX, United StatesChaperonins are biological nanomachines that help newly translated proteins to fold by rescuing them from kinetically trapped misfolded states. Protein folding assistance by the chaperonin machinery is obligatory in vivo for a subset of proteins in the bacterial proteome. Chaperonins are large oligomeric complexes, with unusual seven fold symmetry (group I) or eight/nine fold symmetry (group II), that form double-ring constructs, enclosing a central cavity that serves as the folding chamber. Dramatic large-scale conformational changes, that take place during ATP-driven cycles, allow chaperonins to bind misfolded proteins, encapsulate them into the expanded cavity and release them back into the cellular environment, regardless of whether they are folded or not. The theory associated with the iterative annealing mechanism, which incorporated the conformational free energy landscape description of protein folding, quantitatively explains most, if not all, the available data. Misfolded conformations are associated with low energy minima in a rugged energy landscape. Random disruptions of these low energy conformations result in higher free energy, less folded, conformations that can stochastically partition into the native state. Two distinct mechanisms of annealing action have been described. Group I chaperonins (GroEL homologues in eubacteria and endosymbiotic organelles), recognize a large number of misfolded proteins non-specifically and operate through highly coordinated cooperative motions. By contrast, the less well understood group II chaperonins (CCT in Eukarya and thermosome/TF55 in Archaea), assist a selected set of substrate proteins. Sequential conformational changes within a CCT ring are observed, perhaps promoting domain-by-domain substrate folding. Chaperonins are implicated in bacterial infection, autoimmune disease, as well as protein aggregation and degradation diseases. Understanding the chaperonin mechanism and the specific proteins they rescue during the cell cycle is important not only for the fundamental aspect of protein folding in the cellular environment, but also for effective therapeutic strategies.https://www.frontiersin.org/articles/10.3389/fmolb.2022.1071168/fullGroELGroESchaperoninssubstrate recognitionfolding assistancemisfolding |
| spellingShingle | George Stan George H. Lorimer D. Thirumalai D. Thirumalai Friends in need: How chaperonins recognize and remodel proteins that require folding assistance Frontiers in Molecular Biosciences GroEL GroES chaperonins substrate recognition folding assistance misfolding |
| title | Friends in need: How chaperonins recognize and remodel proteins that require folding assistance |
| title_full | Friends in need: How chaperonins recognize and remodel proteins that require folding assistance |
| title_fullStr | Friends in need: How chaperonins recognize and remodel proteins that require folding assistance |
| title_full_unstemmed | Friends in need: How chaperonins recognize and remodel proteins that require folding assistance |
| title_short | Friends in need: How chaperonins recognize and remodel proteins that require folding assistance |
| title_sort | friends in need how chaperonins recognize and remodel proteins that require folding assistance |
| topic | GroEL GroES chaperonins substrate recognition folding assistance misfolding |
| url | https://www.frontiersin.org/articles/10.3389/fmolb.2022.1071168/full |
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