{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,12]],"date-time":"2026-05-12T07:17:45Z","timestamp":1778570265687,"version":"3.51.4"},"update-to":[{"DOI":"10.1371\/journal.pgen.1010334","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2022,9,9]],"date-time":"2022-09-09T00:00:00Z","timestamp":1662681600000}}],"reference-count":78,"publisher":"Public Library of Science (PLoS)","issue":"8","license":[{"start":{"date-parts":[[2022,8,29]],"date-time":"2022-08-29T00:00:00Z","timestamp":1661731200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Department of Biotechnology","award":["BT\/COE\/34\/SP15219\/2015, DT.20\/11\/2015"],"award-info":[{"award-number":["BT\/COE\/34\/SP15219\/2015, DT.20\/11\/2015"]}]},{"DOI":"10.13039\/100000865","name":"Bill and Melinda Gates Foundation","doi-asserted-by":"publisher","award":["INV-005948"],"award-info":[{"award-number":["INV-005948"]}],"id":[{"id":"10.13039\/100000865","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Department of Science and Technology-Fund for Improvement of S&T Infrastructure (DST-FIST), India"},{"name":"University Grants Commission, India"},{"DOI":"10.13039\/501100004541","name":"Ministry of Education, India","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004541","id-type":"DOI","asserted-by":"publisher"}]},{"name":"DBT IISc Partnership Program"},{"DOI":"10.13039\/501100004541","name":"Ministry of Education, India","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004541","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004541","name":"Ministry of Education, India","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004541","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Department of Biotechnology","award":["BT\/IN\/EU-INF\/15\/RV\/19-20"],"award-info":[{"award-number":["BT\/IN\/EU-INF\/15\/RV\/19-20"]}]},{"name":"Department of Science and Technology-Science and Engineering Research Board","award":["PDF\/2017\/002641"],"award-info":[{"award-number":["PDF\/2017\/002641"]}]},{"DOI":"10.13039\/501100009053","name":"The Wellcome Trust DBT India Alliance","doi-asserted-by":"publisher","award":["IA\/E\/16\/1\/502999"],"award-info":[{"award-number":["IA\/E\/16\/1\/502999"]}],"id":[{"id":"10.13039\/501100009053","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosgenetics.org"],"crossmark-restriction":false},"short-container-title":["PLoS Genet"],"abstract":"<jats:p>\n                    Most amino acid substitutions in a protein either lead to partial loss-of-function or are near neutral. Several studies have shown the existence of second-site mutations that can rescue defects caused by diverse loss-of-function mutations. Such global suppressor mutations are key drivers of protein evolution. However, the mechanisms responsible for such suppression remain poorly understood. To address this, we characterized multiple suppressor mutations both in isolation and in combination with inactive mutants. We examined six global suppressors of the bacterial toxin CcdB, the known M182T global suppressor of TEM-1 \u03b2-lactamase, the N239Y global suppressor of p53-DBD and three suppressors of the SARS-CoV-2 spike Receptor Binding Domain. When coupled to inactive mutants, they promote increased\n                    <jats:italic>in-vivo<\/jats:italic>\n                    solubilities as well as regain-of-function phenotypes. In the case of CcdB, where novel suppressors were isolated, we determined the crystal structures of three such suppressors to obtain insight into the specific molecular interactions responsible for the observed effects. While most individual suppressors result in small stability enhancements relative to wildtype, which can be combined to yield significant stability increments, thermodynamic stabilisation is neither necessary nor sufficient for suppressor action. Instead, in diverse systems, we observe that individual global suppressors greatly enhance the foldability of buried site mutants, primarily through increase in refolding rate parameters measured\n                    <jats:italic>in vitro<\/jats:italic>\n                    . In the crowded intracellular environment, mutations that slow down folding likely facilitate off-pathway aggregation. We suggest that suppressor mutations that accelerate refolding can counteract this, enhancing the yield of properly folded, functional protein\n                    <jats:italic>in vivo<\/jats:italic>\n                    .\n                  <\/jats:p>","DOI":"10.1371\/journal.pgen.1010334","type":"journal-article","created":{"date-parts":[[2022,8,29]],"date-time":"2022-08-29T13:47:43Z","timestamp":1661780863000},"page":"e1010334","update-policy":"https:\/\/doi.org\/10.1371\/journal.pgen.corrections_policy","source":"Crossref","is-referenced-by-count":15,"title":["Mechanistic insights into global suppressors of protein folding defects"],"prefix":"10.1371","volume":"18","author":[{"given":"Gopinath","family":"Chattopadhyay","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jayantika","family":"Bhowmick","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1838-5362","authenticated-orcid":true,"given":"Kavyashree","family":"Manjunath","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shahbaz","family":"Ahmed","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7808-8298","authenticated-orcid":true,"given":"Parveen","family":"Goyal","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0823-7577","authenticated-orcid":true,"given":"Raghavan","family":"Varadarajan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2022,8,29]]},"reference":[{"key":"pgen.1010334.ref001","doi-asserted-by":"crossref","first-page":"e09532","DOI":"10.7554\/eLife.09532","article-title":"Residue proximity information and protein model discrimination using saturation-suppressor mutagenesis","volume":"4","author":"A Sahoo","year":"2015","journal-title":"Elife"},{"key":"pgen.1010334.ref002","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1371\/journal.pgen.1004918","article-title":"Combining Natural Sequence Variation with High Throughput Mutational Data to Reveal Protein Interaction Sites","volume":"11","author":"D Melamed","year":"2015","journal-title":"PLoS Genet."},{"key":"pgen.1010334.ref003","doi-asserted-by":"crossref","first-page":"1323","DOI":"10.1534\/genetics.104.037259","article-title":"The coupon collector and the suppressor mutation: Estimating the number of compensatory mutations by maximum likelihood","volume":"170","author":"A Poon","year":"2005","journal-title":"Genetics"},{"key":"pgen.1010334.ref004","doi-asserted-by":"crossref","first-page":"16858","DOI":"10.1073\/pnas.1209751109","article-title":"A fundamental protein property, thermodynamic stability, revealed solely from large-scale measurements of protein function","volume":"109","author":"CL Araya","year":"2012","journal-title":"Proc Natl Acad Sci"},{"key":"pgen.1010334.ref005","first-page":"53","article-title":"Phage lambda repressor revertants. 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