title: A Potential Structural Switch for Regulating DNA-Binding by TEAD Transcription Factors.
abstract: TEA domain (TEAD) transcription factors are essential for the normal development of eukaryotes and are the downstream effectors of the Hippo tumor suppressor pathway. Whereas our earlier work established the three-dimensional structure of the highly conserved DNA-binding domain using solution NMR spectroscopy, the structural basis for regulating the DNA-binding activity remains unknown. Here, we present the X-ray crystallographic structure and activity of a TEAD mutant containing a truncated L1 loop, ΔL1 TEAD DBD. Unexpectedly, the three-dimensional structure of the ΔL1 TEAD DBD reveals a helix-swapped homodimer wherein helix 1 is swapped between monomers. Furthermore, each three-helix bundle in the domain-swapped dimer is a structural homolog of MYB-like domains. Our investigations of the DNA-binding activity reveal that although the formation of the three-helix bundle by the ΔL1 TEAD DBD is sufficient for binding to an isolated M-CAT-like DNA element, multimeric forms are deficient for cooperative binding to tandemly duplicated elements, indicating that the L1 loop contributes to the DNA-binding activity of TEAD. These results suggest that switching between monomeric and domain-swapped forms may regulate DNA selectivity of TEAD proteins.
authors.affiliation: Jeju National University, 102 Jejudaehak-ro, Jeju-si, Jeju Special Self-Governing Province, 690-756, South Korea.
authors.forename: Dong-Sun
authors.initials: DS
authors.lastname: Lee
authors.affiliation: Global Phasing Limited, Sheraton House, Castle Park, Cambridge CB3 0AX, UK.
authors.forename: Clemens
authors.initials: C
authors.lastname: Vonrhein
authors.affiliation: Pennington Biomedical Research Center, 6400 Perkins Rd, Baton Rouge, LA 70808, USA.
authors.forename: Diana
authors.initials: D
authors.lastname: Albarado
authors.affiliation: University of Maryland School of Pharmacy, 20 N. Pine St., Baltimore, MD 21201, USA.
authors.forename: C S
authors.initials: CS
authors.lastname: Raman
authors.affiliation: University of Maryland School of Pharmacy, 20 N. Pine St., Baltimore, MD 21201, USA. Electronic address: sudha.veeraraghavan@gmail.com.
authors.forename: Sudha
authors.initials: S
authors.lastname: Veeraraghavan
mesh_terms: D000595:Amino Acid Sequence; D004247:DNA / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D019281:Dimerization; D004926:Escherichia coli / Q000378:metabolism; D011485:Protein Binding / Q000502:physiology; D017434:Protein Structure, Tertiary; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; D014157:Transcription Factors; D004247:DNA
keywords: Hippo pathway; TEAD; X-ray crystallography; domain swapping; transcription factor