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Insights into Molecular Diversity within the FUS/EWS/TAF15 Protein Family: Unraveling Phase Separation of the N-Terminal Low-Complexity Domain from RNA-Binding Protein EWS.
Johnson, Courtney N; Sojitra, Kandarp A; Sohn, Erich J; Moreno-Romero, Alma K; Baudin, Antoine; Xu, Xiaoping; Mittal, Jeetain; Libich, David S.
Affiliation
  • Johnson CN; Greehey Children's Cancer Research Institute, The University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229, United States.
  • Sojitra KA; Department of Biochemistry and Structural Biology, The University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229, United States.
  • Sohn EJ; Artie McFerrin Department of Chemical Engineering, Texas A&M University, College Station, Texas 77843, United States.
  • Moreno-Romero AK; Greehey Children's Cancer Research Institute, The University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229, United States.
  • Baudin A; Department of Biochemistry and Structural Biology, The University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229, United States.
  • Xu X; Greehey Children's Cancer Research Institute, The University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229, United States.
  • Mittal J; Department of Biochemistry and Structural Biology, The University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229, United States.
  • Libich DS; Greehey Children's Cancer Research Institute, The University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229, United States.
J Am Chem Soc ; 146(12): 8071-8085, 2024 03 27.
Article in En | MEDLINE | ID: mdl-38492239
ABSTRACT
The FET protein family, comprising FUS, EWS, and TAF15, plays crucial roles in mRNA maturation, transcriptional regulation, and DNA damage response. Clinically, they are linked to Ewing family tumors and neurodegenerative diseases such as amyotrophic lateral sclerosis. The fusion protein EWSFLI1, the causative mutation of Ewing sarcoma, arises from a genomic translocation that fuses a portion of the low-complexity domain (LCD) of EWS (EWSLCD) with the DNA binding domain of the ETS transcription factor FLI1. This fusion protein modifies transcriptional programs and disrupts native EWS functions, such as splicing. The exact role of the intrinsically disordered EWSLCD remains a topic of active investigation, but its ability to phase separate and form biomolecular condensates is believed to be central to EWSFLI1's oncogenic properties. Here, we used paramagnetic relaxation enhancement NMR, microscopy, and all-atom molecular dynamics (MD) simulations to better understand the self-association and phase separation tendencies of the EWSLCD. Our NMR data and mutational analysis suggest that a higher density and proximity of tyrosine residues amplify the likelihood of condensate formation. MD simulations revealed that the tyrosine-rich termini exhibit compact conformations with unique contact networks and provided critical input on the relationship between contacts formed within a single molecule (intramolecular) and inside the condensed phase (intermolecular). These findings enhance our understanding of FET proteins' condensate-forming capabilities and underline differences between EWS, FUS, and TAF15.
Subject(s)

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Sarcoma, Ewing / TATA-Binding Protein Associated Factors Limits: Humans Language: En Journal: J Am Chem Soc / Journal of the american chemical society / J. am. chem. soc Year: 2024 Document type: Article Affiliation country: Estados Unidos Country of publication: Estados Unidos

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Sarcoma, Ewing / TATA-Binding Protein Associated Factors Limits: Humans Language: En Journal: J Am Chem Soc / Journal of the american chemical society / J. am. chem. soc Year: 2024 Document type: Article Affiliation country: Estados Unidos Country of publication: Estados Unidos