| Title: |
Evolutionary turnover of key amino acids explains conservation of function without conservation of sequence in transcriptional activation domains |
| Authors: |
LeBlanc, Claire J.; Stefani, Jordan; Soriano, Melvin; Lam, Angelica W. Y.; Zintel, Marissa A.; Kotha, Sanjana R.; Chase, Emily P.; Pimentel-Solorio, Giovani; Vunnum, Aditya; Hu, Gean; Flug, Katherine L.; Fultineer, Aaron; Hummel, Niklas; Staller, Max V. |
| Contributors: |
Guertin, Michael J.; NIH; UC Berkeley URAP; UC Berkeley SEED Scholars Program; UC Berkeley SURF; UC Berkeley Rose Hill.; UC Berkeley BSP scholars; McNair Scholars; Burroughs Wellcome Fund PDEP; Simons Foundation; NSF |
| Source: |
PLOS Genetics ; volume 22, issue 3, page e1012069 ; ISSN 1553-7404 |
| Publisher Information: |
Public Library of Science (PLoS) |
| Publication Year: |
2026 |
| Collection: |
PLOS Publications (via CrossRef) |
| Description: |
In folded protein domains, protein function is frequently more conserved than amino acid sequence because highly diverged sequences can fold into equivalent 3D structures with identical function. During evolution, intrinsically disordered protein regions (IDRs) often experience rapid amino acid sequence divergence, but because they do not fold into stable 3D structures, it remains largely unknown when and how function is conserved. As a model system for studying the evolution of IDRs, we examined transcriptional activation domains, the regions of transcription factors that bind to coactivator complexes. We systematically identified activation domains on 502 homologs of the transcriptional activator Gcn4 spanning 600 MY of fungal evolution in the Ascomycota. We found that the central activation domain shows strong conservation of function without conservation of sequence. This conservation of function without conservation of sequence arises from evolutionary turnover (gain and loss) at two length scales. Within the central activation domain, we see turnover of acidic and aromatic residues, but primarily loss of short linear motifs. In the full-length transcription factor, we see turnover of entire activation domains. Stabilizing selection and evolutionary turnover at multiple length scales are likely a general mechanism for conservation of function without conservation of sequence in IDRs. |
| Document Type: |
article in journal/newspaper |
| Language: |
English |
| DOI: |
10.1371/journal.pgen.1012069 |
| Availability: |
https://doi.org/10.1371/journal.pgen.1012069; https://dx.plos.org/10.1371/journal.pgen.1012069 |
| Rights: |
http://creativecommons.org/licenses/by/4.0/ |
| Accession Number: |
edsbas.9CF666E6 |
| Database: |
BASE |