Coevolution-derived native and non-native contacts determine the emergence of a novel fold in a universally conserved family of transcription factors

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dc.contributor.authorGalaz-Davison, Pablo
dc.contributor.authorFerreiro, Diego U.
dc.contributor.authorRamirez-Sarmiento, Cesar A.
dc.date.accessioned2025-01-20T21:07:19Z
dc.date.available2025-01-20T21:07:19Z
dc.date.issued2022
dc.description.abstractThe NusG protein family is structurally and functionally conserved in all domains of life. Its members directly bind RNA polymerases and regulate transcription processivity and termination. RfaH, a divergent sub-family in its evolutionary history, is known for displaying distinct features than those in NusG proteins, which allows them to regulate the expression of virulence factors in enterobacteria in a DNA sequence-dependent manner. A striking feature is its structural interconversion between an active fold, which is the canonical NusG three-dimensional structure, and an autoinhibited fold, which is distinctively novel. How this novel fold is encoded within RfaH sequence to encode a metamorphic protein remains elusive. In this work, we used publicly available genomic RfaH protein sequences to construct a complete multiple sequence alignment, which was further augmented with metagenomic sequences and curated by predicting their secondary structure propensities using JPred. Coevolving pairs of residues were calculated from these sequences using plmDCA and GREMLIN, which allowed us to detect the enrichment of key metamorphic contacts after sequence filtering. Finally, we combined our coevolutionary predictions with molecular dynamics to demonstrate that these interactions are sufficient to predict the structures of both native folds, where coevolutionary-derived non-native contacts may play a key role in achieving the compact RfaH novel fold. All in all, emergent coevolutionary signals found within RfaH sequences encode the autoinhibited and active folds of this protein, shedding light on the key interactions responsible for the action of this metamorphic protein.
dc.fuente.origenWOS
dc.identifier.doi10.1002/pro.4337
dc.identifier.eissn1469-896X
dc.identifier.issn0961-8368
dc.identifier.urihttps://doi.org/10.1002/pro.4337
dc.identifier.urihttps://repositorio.uc.cl/handle/11534/93407
dc.identifier.wosidWOS:000798702900001
dc.issue.numero6
dc.language.isoen
dc.revistaProtein science
dc.rightsacceso restringido
dc.subjectdirect coupling analysis
dc.subjectevolution
dc.subjectfold-switch
dc.subjectmetamorphic proteins
dc.subjectprotein folding
dc.subjecttranscription factor
dc.subject.ods03 Good Health and Well-being
dc.subject.odspa03 Salud y bienestar
dc.titleCoevolution-derived native and non-native contacts determine the emergence of a novel fold in a universally conserved family of transcription factors
dc.typeartículo
dc.volumen31
sipa.indexWOS
sipa.trazabilidadWOS;2025-01-12
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