{"doi":"10.1016/j.jbc.2021.100293","title":"Decrypting the chaperone code","abstract":"The ongoing COVID pandemic has disrupted the ability to hold scientific conferences in person. Despite this, over 200 people from across the world attended The First International Symposium on the Chaperone Code, which was held virtually on October 28 to 29, 2020. The meeting highlighted the many ways that posttranslational modifications (PTMs) on molecular chaperones regulate their function to control proteostasis in diverse organisms. Cells are continuously exposed to a variety of internal and external stressors that induce protein misfolding. To respond and recover from these stresses, cells express a myriad of molecular chaperone and co-chaperone paralogs that aid in folding, refolding, stabilization, activation, and transport of a large proportion of the proteome (“clients”). While chaperones have been extensively studied for over 40 years, the majority of studies have focused on chaperone actions, ATPase cycle regulation, and in vitro folding mechanisms. With the exponential improvement in proteomic technologies over the past 10 years, a huge number of PTMs have been uncovered on chaperones including phosphorylation, acetylation, methylation, SUMOylation, and ubiquitination. Despite the identification of these sites, the respective roles and roles of the modifications (collectively known as the Chaperone Code, Fig. 1) are poorly understood. The inaugural meeting on the Chaperone Code brought together experts from diverse fields ranging from chaperone mechanisms to signal transduction to discuss their latest exciting insights on the Chaperone Code. In this report, we highlight several of these findings in this emerging field of chaperone biology. Heat shock protein 90 (Hsp90) is a molecular chaperone involved in folding, stability, and activity of more than 300 proteins also known as clients. Many of these clients are involved in various maladies including cancer, neurodegenerative and infectious diseases (1Schopf F.H. Biebl M.M. Buchner J. The HSP90 chaperone machinery.Nat. Rev. Mol. Cell Biol. 2017; 18: 345-360Crossref PubMed Scopus (475) Google Scholar, 2Woodford M.R. Dunn D.M. Ciciarelli J.G. Beebe K. Neckers L. Mollapour M. Targeting Hsp90 in non-cancerous maladies.Curr. Top Med. Chem. 2016; 16: 2792-2804Crossref PubMed Scopus (9) Google Scholar). Therefore, targeting Hsp90 in preclinical studies and clinical trials in these diseases has been actively pursued (3Neckers L. Workman P. Hsp90 molecular chaperone inhibitors: Are we there yet?.Clin. Cancer Res. 2012; 18: 64-76Crossref PubMed Scopus (685) Google Scholar). Hsp90 chaperone function is linked to its intrinsic ATPase activity of Hsp90. This activity is enhanced by the co-chaperone Aha1 (1Schopf F.H. Biebl M.M. Buchner J. The HSP90 chaperone machinery.Nat. Rev. Mol. Cell Biol. 2017; 18: 345-360Crossref PubMed Scopus (475) Google Scholar). Len Neckers (National Cancer Institute, USA) showed that phosphorylation of a highly conserved Tyr313 in the middle domain of human Hsp90α is important for initial binding of Aha1 (4Xu W. Beebe K. Chavez J.D. Boysen M. Lu Y. Zuehlke A.D. Keramisanou D. Trepel J.B. Prodromou C. Mayer M.P. Bruce J.E. Gelis I. Neckers L. Hsp90 middle domain phosphorylation initiates a complex conformational program to recruit the ATPase-stimulating cochaperone Aha1.Nat. Commun. 2019; 10: 2574Crossref PubMed Scopus (11) Google Scholar). Phosphorylation of Tyr313 appears to provide a phosphorylation-sensitive conformational switch that initiates Aha1 C-domain recruitment to the Hsp90 middle (M) domain and consequent stimulation of ATPase activity. This binding pose of the Aha1 C-domain to Hsp90 M-domain, which was unexpected based on previous models, is supported by recently reported orthogonal cryo-EM data (4Xu W. Beebe K. Chavez J.D. Boysen M. Lu Y. Zuehlke A.D. Keramisanou D. Trepel J.B. Prodromou C. Mayer M.P. Bruce J.E. Gelis I. Neckers L. Hsp90 middle domain phosphorylation initiates a complex conformational program to recruit the ATPase-stimu","journal":"Journal of Biological Chemistry","year":2021,"id":173168,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":24,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9563,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":346998,"name":"Dimitra Bourboulia","orcid":"0000-0002-8567-2775","position":1,"is_corresponding":false},{"id":347006,"name":"Mehdi Mollapour","orcid":"0000-0002-2144-1361","position":2,"is_corresponding":false},{"id":444005,"name":"Andrew W. Truman","orcid":"0000-0002-6409-3723","position":0,"is_corresponding":true}],"reference_count":36,"raw_metadata":null,"created_at":"2026-07-18T23:46:45.768135Z","pmid":"33837727","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,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}