title: Palmitoylation of TEAD Transcription Factors Is Required for Their Stability and Function in Hippo Pathway Signaling.
abstract: The Hippo signaling pathway is responsible for regulating the function of TEAD family transcription factors in metazoans. TEADs, with their co-activators YAP/TAZ, are critical for controlling cell differentiation and organ size through their transcriptional activation of genes involved in cell growth and proliferation. Dysregulation of the Hippo pathway has been implicated in multiple forms of cancer. Here, we identify a novel form of regulation of TEAD family proteins. We show that human TEADs are palmitoylated at a universally conserved cysteine, and report the crystal structures of the human TEAD2 and TEAD3 YAP-binding domains in their palmitoylated forms. These structures show a palmitate bound within a highly conserved hydrophobic cavity at each protein's core. Our findings also demonstrate that this modification is required for proper TEAD folding and stability, indicating a potential new avenue for pharmacologically regulating the Hippo pathway through the modulation of TEAD palmitoylation.
authors.affiliation: Department of Structural Biology, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Cameron L
authors.initials: CL
authors.lastname: Noland
authors.affiliation: Center for Advanced Light Microscopy, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Sarah
authors.initials: S
authors.lastname: Gierke
authors.affiliation: Department of Protein Chemistry, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Paul D
authors.initials: PD
authors.lastname: Schnier
authors.affiliation: Department of Structural Biology, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Murray
authors.affiliation: Department of Protein Chemistry, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Wendy N
authors.initials: WN
authors.lastname: Sandoval
authors.affiliation: Center for Advanced Light Microscopy, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Meredith
authors.initials: M
authors.lastname: Sagolla
authors.affiliation: Department of Discovery Oncology, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Anwesha
authors.initials: A
authors.lastname: Dey
authors.affiliation: Department of Early Discovery Biochemistry, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Rami N
authors.initials: RN
authors.lastname: Hannoush
authors.affiliation: Department of Early Discovery Biochemistry, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA. Electronic address: fairbrother.wayne@gene.com.
authors.forename: Wayne J
authors.initials: WJ
authors.lastname: Fairbrother
authors.affiliation: Department of Early Discovery Biochemistry, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA. Electronic address: cunningham.christian@gene.com.
authors.forename: Christian N
authors.initials: CN
authors.lastname: Cunningham
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000595:Amino Acid Sequence; D003545:Cysteine / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000737:chemistry* / Q000378:metabolism; D006367:HeLa Cells; D000090683:Hippo Signaling Pathway; D006801:Humans; D054878:Lipoylation; D008969:Molecular Sequence Data; D009685:Nuclear Envelope / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D011485:Protein Binding; D017510:Protein Folding; D011499:Protein Processing, Post-Translational; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D055550:Protein Stability; D015398:Signal Transduction; D000091262:TEA Domain Transcription Factors; D014157:Transcription Factors / Q000737:chemistry* / Q000378:metabolism; D000091102:YAP-Signaling Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D004268:DNA-Binding Proteins; D010750:Phosphoproteins; D000091262:TEA Domain Transcription Factors; C101205:TEAD2 protein, human; C106169:TEAD3 protein, human; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins; C088374:YAP1 protein, human; D017346:Protein Serine-Threonine Kinases; D003545:Cysteine