A Sveinsson's chorioretinal atrophy-associated missense mutation in mouse Tead1 affects its interaction with the co-factors YAP and TAZ.
Sveinsson's chorioretinal atrophy (SCRA) is an autosomal dominant eye disease characterized by bilateral chorioretinal degeneration. A missense mutation in the gene encoding the transcription factor TEAD1/TEF-1 (Y421H) is genetically linked to SCRA, but the mechanisms of pathology remain unclear. To study the molecular mechanisms underlying SCRA, a missense mutation corresponding to Y421H in human TEAD1 was introduced into mouse Tead1 (Y410H), and a functional analysis of the mutant protein was performed in RPE-J cells. The missense mutation reduced the ability of Tead1 to interact with the co-factors YAP and TAZ, but not with the co-factors Vgl-1, -2, and -3, in a mammalian two-hybrid assay. A GST pull-down assay showed that the direct interaction between Tead1 and YAP or TAZ was lost owing to the mutation. Amino acid substitutions at position 410 of Tead1 revealed the essentiality of this tyrosine residue to the interaction. The Y410H mutation also abolished the transcriptional activity of Tead1 under the co-expression of YAP or TAZ. These results suggest that SCRA pathogenesis may be due to a loss-of-function of TEAD1 affecting the regulation of its target genes.
Kitagawa
Michinori
M
Division of Molecular Neurobiology, Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto 860-0811, Japan. kitagawa@gpo.kumamoto-u.ac.jp
D000217:Acyltransferases; D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D018797:Cell Cycle Proteins; D002460:Cell Line; D015862:Choroid Diseases / Q000235:genetics* / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D020125:Mutation, Missense; D010750:Phosphoproteins / Q000378:metabolism*; D011506:Proteins / Q000378:metabolism*; D012162:Retinal Degeneration / Q000235:genetics* / Q000378:metabolism; D000091262:TEA Domain Transcription Factors; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism*; D014158:Transcription, Genetic; D000091102:YAP-Signaling Proteins
D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D010750:Phosphoproteins; D011506:Proteins; D000091262:TEA Domain Transcription Factors; C083215:Tead1 protein, mouse; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins; C486223:Yap1 protein, mouse; D000217:Acyltransferases; C486363:tafazzin protein, mouse