Abstract
TEA domain (TEAD) transcription factors bind to the coactivators YAP and TAZ and regulate the transcriptional output of the Hippo pathway, playing critical roles in organ size control and tumorigenesis. Protein S-palmitoylation attaches a fatty acid, palmitate, to cysteine residues and regulates protein trafficking, membrane localization and signaling activities. Using activity-based chemical probes, we discovered that human TEADs possess intrinsic palmitoylating enzyme-like activities and undergo autopalmitoylation at evolutionarily conserved cysteine residues under physiological conditions. We determined the crystal structures of lipid-bound TEADs and found that the lipid chain of palmitate inserts into a conserved deep hydrophobic pocket. Strikingly, palmitoylation did not alter TEAD's localization, but it was required for TEAD's binding to YAP and TAZ and was dispensable for its binding to the Vgll4 tumor suppressor. Moreover, palmitoylation-deficient TEAD mutants impaired TAZ-mediated muscle differentiation in vitro and tissue overgrowth mediated by the Drosophila YAP homolog Yorkie in vivo. Our study directly links autopalmitoylation to the transcriptional regulation of the Hippo pathway.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Amino Acid Sequence
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Animals
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Cell Differentiation / physiology
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Cell Line
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Conserved Sequence
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Cysteine / metabolism*
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism*
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Drosophila Proteins / genetics
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Drosophila Proteins / metabolism
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Fatty Acids, Unsaturated / chemistry
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Hippo Signaling Pathway
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Humans
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Lipoylation*
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Models, Molecular
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Molecular Sequence Data
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Muscle Fibers, Skeletal / cytology
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Muscle Fibers, Skeletal / metabolism
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Nuclear Proteins / genetics
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Nuclear Proteins / metabolism*
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Palmitates / chemistry
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Protein Binding
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Protein Serine-Threonine Kinases / metabolism*
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Protein Transport
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Sequence Alignment
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Signal Transduction*
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TEA Domain Transcription Factors
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Trans-Activators / genetics
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Trans-Activators / metabolism
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Transcription Factors / genetics
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Transcription Factors / metabolism*
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YAP-Signaling Proteins
Substances
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DNA-Binding Proteins
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Dis3 protein, Drosophila
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Drosophila Proteins
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Fatty Acids, Unsaturated
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Nuclear Proteins
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Palmitates
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TEA Domain Transcription Factors
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TEAD1 protein, human
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TEAD2 protein, human
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Trans-Activators
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Transcription Factors
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YAP-Signaling Proteins
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Yki protein, Drosophila
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15-hexadecynoic acid
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Protein Serine-Threonine Kinases
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Cysteine