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Structure. 2016 Jan 5;24(1):179-186. doi: 10.1016/j.str.2015.11.005. Epub 2015 Dec 24.

Palmitoylation of TEAD Transcription Factors Is Required for Their Stability and Function in Hippo Pathway Signaling.

Author information

1
Department of Structural Biology, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
2
Center for Advanced Light Microscopy, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
3
Department of Protein Chemistry, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
4
Department of Discovery Oncology, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
5
Department of Early Discovery Biochemistry, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
6
Department of Early Discovery Biochemistry, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA. Electronic address: fairbrother.wayne@gene.com.
7
Department of Early Discovery Biochemistry, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA. Electronic address: cunningham.christian@gene.com.

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.

PMID:
26724994
DOI:
10.1016/j.str.2015.11.005
[Indexed for MEDLINE]
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