{"doi":"10.1126/science.aac4354","title":"In vivo aspects of protein folding and quality control","abstract":"<jats:sec>\n                    <jats:title>BACKGROUND</jats:title>\n                    <jats:p>Proteins are synthesized on ribosomes as linear chains of amino acids and must fold into unique three-dimensional structures to fulfill their biological functions. Protein folding is intrinsically error-prone, and how it is accomplished efficiently represents a problem of great biological and medical importance. During folding, the nascent polypeptide must navigate a complex energy landscape. As a result, misfolded molecules may accumulate that expose hydrophobic amino acid residues and thus are in danger of forming potentially toxic aggregates. To ensure efficient folding and prevent aggregation, cells in all domains of life express various classes of proteins called molecular chaperones. These proteins receive the nascent polypeptide chain emerging from the ribosome and guide it along a productive folding pathway. Because proteins are structurally dynamic, constant surveillance of the proteome by an integrated network of chaperones and protein degradation machineries, the proteostasis network (PN), is required to maintain protein homeostasis in a range of external and endogenous stress conditions.</jats:p>\n                  </jats:sec>\n                  <jats:sec>\n                    <jats:title>ADVANCES</jats:title>\n                    <jats:p>Over the past decade, we have gained substantial new insight into the overall behavior of the PN and the molecular mechanics of its components. Advances in structural biology and biophysical approaches have allowed chaperone mechanisms to be interrogated at an unprecedented level of detail. Recent work has provided fascinating insight into the process of protein folding on the ribosome and revealed how highly allosteric chaperones such as the heat shock protein 70 (Hsp70), Hsp90, and chaperonin systems modulate the folding energy landscapes of their protein clients. Studies of chaperone systems from bacteria and eukaryotes have revealed common principles underlying the organization of chaperone networks in different domains of life. Recently, we have begun to appreciate the relative complexity of eukaryotic chaperones and are starting to understand how eukaryotes deal with the challenge of folding a large proteome enriched in multidomain proteins. At the cellular level, the response of the PN to conformational stress, aging, and diseases of aberrant protein folding has been an area of intense investigation. Importantly, the capacity of the PN declines during aging and this leads to dysfunction of specific cell types and tissues, rendering the organism susceptible to chronic diseases. Among these, neurodegenerative syndromes associated with protein aggregation are increasingly prevalent in the aging human population. Notably, the accumulation of toxic protein aggregates is both a consequence and a cause of PN decline, driving a vicious cycle that ultimately leads to proteostasis collapse.</jats:p>\n                  </jats:sec>\n                  <jats:sec>\n                    <jats:title>OUTLOOK</jats:title>\n                    <jats:p>A new view of protein folding is emerging, whereby the energy landscapes that proteins navigate during folding in vivo may differ substantially from those observed during refolding in vitro. From the ribosome through to the major chaperone systems, the nascent protein interacts with factors that modulate its folding pathway. Future work should focus on obtaining the high-resolution structural and kinetic information necessary to define the pathways of protein folding during translation, and in association with molecular chaperones. Organisms have evolved various mechanisms to deal with misfolded and aggregated proteins to maintain proteostasis. It is becoming increasingly clear that besides removing these proteins by degradation, cells also strategically sequester them into transient or stable aggregates, often in defined cellular locations. Much remains to be understood about how this cellular decision-making occurs at a molecular level and how dysregulation of these mechanisms leads to proteotoxicity. From a medical perspective, the intimate relationship between proteostasis and disease, aging, and neurodegeneration makes components of the PN logical drug targets, with the goal of promoting healthy aging. Pharmacological manipulation of the PN will require a detailed understanding of how the network responds to perturbation and how its different components cooperate.</jats:p>\n                    <jats:fig fig-type=\"figure\" orientation=\"portrait\" position=\"float\">\n                      <jats:caption>\n                        <jats:title>Molecular chaperones are key players in the cellular proteostasis network and serve to maintain a balanced proteome.</jats:title>\n                        <jats:p>They promote the folding of newly synthesized proteins, function in conformational maintenance, and prevent potentially toxic off-pathway aggregation. Chaperones also cooperate with other components of the proteostasis network, such as the proteasome system and autophagy, in the removal of terminally misfolded and aggregated proteins through proteolytic degradation.</jats:p>\n                      </jats:caption>\n                      <jats:graphic xmlns:xlink=\"http://www.w3.org/1999/xlink\" orientation=\"portrait\" position=\"float\" xlink:href=\"353_aac4354_Fa.jpeg\"/>\n                    </jats:fig>\n                  </jats:sec>","journal":"Science","year":2016,"id":22628,"datarank":9.10966317434963,"base_score":7.301147805856032,"endowment":7.301147805856032,"self_citation_contribution":1.095172170878405,"citation_network_contribution":8.014491003471225,"self_endowment_contribution":1.095172170878405,"citer_contribution":8.014491003471225,"corpus_percentile":null,"corpus_rank":null,"citation_count":1481,"citer_count":200,"citers_with_citation_signal":200,"citers_with_endowment":200,"datacite_reuse_total":25,"is_dataset":false,"is_dataset_confidence":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":141586,"name":"Manajit Hayer-Hartl","orcid":null,"position":1,"is_corresponding":false},{"id":141587,"name":"F. Ulrich Hartl","orcid":null,"position":2,"is_corresponding":false},{"id":141628,"name":"David Balchin","orcid":null,"position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"base_score":7.301147805856032,"endowment":7.301147805856032,"datacite_reuse_total":25,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"27365453","pmcid":null,"openalex_id":"https://openalex.org/W2473711714","authors":[],"funders":[{"funder_name":"European Commission","grant_id":"318987","title":"Toxic protein aggregation in neurodegeneration"},{"funder_name":"Minerva Foundation","grant_id":"","title":null},{"funder_name":"Center for Integrated Protein Science Munich (CiPSM)","grant_id":"","title":null},{"funder_name":"European Research Council","grant_id":"","title":null},{"funder_name":"Munich Cluster for Systems Neurology (SyNergy)","grant_id":"","title":null}],"total_grants":5,"fwci":78.3124,"citation_percentile":0.99996621,"influential_citations":42,"citation_trend":[{"year":2016,"count":20},{"year":2017,"count":98},{"year":2018,"count":145},{"year":2019,"count":147},{"year":2020,"count":169},{"year":2021,"count":188},{"year":2022,"count":182},{"year":2023,"count":190},{"year":2024,"count":152},{"year":2025,"count":137},{"year":2026,"count":53}],"oa_status":"green","license":"other-oa","oa_locations":[{"url":"https://hdl.handle.net/11858/00-001M-0000-002B-0858-8","host_type":"repository"},{"url":"https://pure.mpg.de/pubman/item/item_2316631_5/component/file_2316629/Balchin%20et%20al_Postprint_aac4354.pdf","host_type":"GREEN"},{"url":"https://hdl.handle.net/11858/00-001M-0000-002B-0858-8","host_type":"repository"},{"url":"https://www.science.org/doi/pdf/10.1126/science.aac4354","host_type":"publisher"},{"url":"http://hdl.handle.net/11858/00-001M-0000-002B-0856-C","host_type":"repository"},{"url":"https://doi.org/10.1126/science.aac4354","host_type":"journal"},{"url":"https://pubmed.ncbi.nlm.nih.gov/27365453","host_type":"repository"},{"url":"https://dx.doi.org/10.1126/science.aac4354","host_type":""},{"url":"http://hdl.handle.net/11858/00-001M-0000-002B-0858-8","host_type":""},{"url":"http://dx.doi.org/10.1126/science.aac4354","host_type":""}],"fields_of_study":["Endoplasmic Reticulum Stress and Disease","Heat shock proteins research","Protein Structure and Dynamics","Biology","Medicine","0301 basic medicine","0303 health sciences","03 medical and health sciences","Aging","Cytosol","HSP72 Heat-Shock Proteins","Homeostasis","Humans","Molecular Chaperones","Molecular Targeted Therapy","Neurodegenerative Diseases","Protein Aggregates","Protein Aggregation, Pathological","Protein Biosynthesis","Protein Conformation","Protein Folding","Proteolysis","Proteostasis Deficiencies","Ribosomes"],"mesh_terms":["Aging","Cytosol","Homeostasis","Humans","Protein Conformation","Ribosomes","Protein Biosynthesis","Protein Folding","Molecular Chaperones","Neurodegenerative Diseases","HSP72 Heat-Shock Proteins","Proteostasis Deficiencies","Molecular Targeted Therapy","Proteolysis","Protein Aggregation, Pathological","Protein Aggregates"],"keywords":["Proteostasis","Protein folding","Proteome","Chaperone (clinical)","Protein aggregation","Ribosome","Biology","Computational biology","Neurodegeneration","Protein quality","Cell biology","Bioinformatics","Biochemistry","Medicine","RNA","Aging","Protein Conformation","HSP72 Heat-Shock Proteins","Neurodegenerative Diseases","Protein Aggregation, Pathological","Protein Aggregates","Cytosol","Protein Biosynthesis","Proteolysis","Homeostasis","Humans","Molecular Targeted Therapy","Proteostasis Deficiencies","Ribosomes","Molecular Chaperones"],"sdg_mappings":[{"sdg_number":3,"sdg_label":"3. Good health"},{"sdg_number":0,"sdg_label":"Affordable and clean energy"}],"linked_datasets":[{"doi":"10.6084/m9.figshare.13620077.v1","title":"Additional file 1 of Translational landscape and protein biogenesis demands of the early secretory pathway in Komagataella phaffii","publisher":"figshare","resource_type":"JournalArticle"},{"doi":"10.6084/m9.figshare.13620077","title":"Additional file 1 of Translational landscape and protein biogenesis demands of the early secretory pathway in Komagataella phaffii","publisher":"figshare","resource_type":"JournalArticle"},{"doi":"10.6084/m9.figshare.13620080.v1","title":"Additional file 2 of Translational landscape and protein biogenesis demands of the early secretory pathway in Komagataella phaffii","publisher":"figshare","resource_type":"JournalArticle"},{"doi":"10.6084/m9.figshare.13620080","title":"Additional file 2 of Translational landscape and protein biogenesis demands of the early secretory pathway in Komagataella phaffii","publisher":"figshare","resource_type":"JournalArticle"},{"doi":"10.6084/m9.figshare.13620092.v1","title":"Additional file 6 of Translational landscape and protein biogenesis demands of the early secretory pathway in Komagataella phaffii","publisher":"figshare","resource_type":"JournalArticle"},{"doi":"10.6084/m9.figshare.13620092","title":"Additional file 6 of Translational landscape and protein biogenesis demands of the early secretory pathway in Komagataella phaffii","publisher":"figshare","resource_type":"JournalArticle"},{"doi":"10.6084/m9.figshare.13620095.v1","title":"Additional file 7 of Translational landscape and protein biogenesis demands of the early secretory pathway in Komagataella phaffii","publisher":"figshare","resource_type":"JournalArticle"},{"doi":"10.6084/m9.figshare.13620095","title":"Additional file 7 of Translational landscape and protein biogenesis demands of the early secretory pathway in Komagataella phaffii","publisher":"figshare","resource_type":"JournalArticle"},{"doi":"10.6084/m9.figshare.13620101.v1","title":"Additional file 9 of Translational landscape and protein biogenesis demands of the early secretory pathway in Komagataella phaffii","publisher":"figshare","resource_type":"JournalArticle"},{"doi":"10.6084/m9.figshare.13620101","title":"Additional file 9 of Translational landscape and protein biogenesis demands of the early secretory pathway in Komagataella phaffii","publisher":"figshare","resource_type":"JournalArticle"},{"doi":"10.6084/m9.figshare.19767871.v1","title":"Additional file 1 of Heat shock protein A4 ablation leads to skeletal muscle myopathy associated with dysregulated autophagy and induced apoptosis","publisher":"figshare","resource_type":"JournalArticle"},{"doi":"10.6084/m9.figshare.19767871","title":"Additional file 1 of Heat shock protein A4 ablation leads to skeletal muscle myopathy associated with dysregulated autophagy and induced apoptosis","publisher":"figshare","resource_type":"JournalArticle"},{"doi":"10.6084/m9.figshare.24123825.v1","title":"Additional file 1 of Prefoldin 2 contributes to mitochondrial morphology and function","publisher":"figshare","resource_type":"JournalArticle"},{"doi":"10.6084/m9.figshare.24123825","title":"Additional file 1 of Prefoldin 2 contributes to mitochondrial morphology and function","publisher":"figshare","resource_type":"JournalArticle"},{"doi":"10.6084/m9.figshare.24123828.v1","title":"Additional file 2 of Prefoldin 2 contributes to mitochondrial morphology and function","publisher":"figshare","resource_type":"JournalArticle"},{"doi":"10.6084/m9.figshare.24123828","title":"Additional file 2 of Prefoldin 2 contributes to mitochondrial morphology and function","publisher":"figshare","resource_type":"JournalArticle"},{"doi":"10.6084/m9.figshare.24123831.v1","title":"Additional file 3 of Prefoldin 2 contributes to mitochondrial morphology and function","publisher":"figshare","resource_type":"JournalArticle"},{"doi":"10.6084/m9.figshare.24123831","title":"Additional file 3 of Prefoldin 2 contributes to mitochondrial morphology and function","publisher":"figshare","resource_type":"JournalArticle"},{"doi":"10.6084/m9.figshare.24123834.v1","title":"Additional file 4 of Prefoldin 2 contributes to mitochondrial morphology and function","publisher":"figshare","resource_type":"JournalArticle"},{"doi":"10.6084/m9.figshare.24123834","title":"Additional file 4 of Prefoldin 2 contributes to mitochondrial morphology and function","publisher":"figshare","resource_type":"JournalArticle"},{"doi":"10.6084/m9.figshare.24123837.v1","title":"Additional file 5 of Prefoldin 2 contributes to mitochondrial morphology and function","publisher":"figshare","resource_type":"JournalArticle"},{"doi":"10.6084/m9.figshare.24123837","title":"Additional file 5 of Prefoldin 2 contributes to mitochondrial morphology and function","publisher":"figshare","resource_type":"JournalArticle"},{"doi":"10.6084/m9.figshare.24123840.v1","title":"Additional file 6 of Prefoldin 2 contributes to mitochondrial morphology and function","publisher":"figshare","resource_type":"JournalArticle"},{"doi":"10.6084/m9.figshare.24123840","title":"Additional file 6 of Prefoldin 2 contributes to mitochondrial morphology and function","publisher":"figshare","resource_type":"JournalArticle"},{"doi":"10.6084/m9.figshare.24123843.v1","title":"Additional file 7 of Prefoldin 2 contributes to mitochondrial morphology and function","publisher":"figshare","resource_type":"JournalArticle"}],"clinical_trials":[],"software_tools":[],"database_accessions":[],"source":"live","citation_network_status":"fetched"},"created_at":"2026-06-07T14:43:20.235877Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}