Chan, PuiYeeHan, XiaoZheng, BaohuiDeRan, MichaelYu, JianzhongJarugumilli, GopalaDeng, HuaPan, DuojiaLuo, XuelianWu, Xu2016-10-112016Chan, PuiYee, Xiao Han, Baohui Zheng, Michael DeRan, Jianzhong Yu, Gopala K. Jarugumilli, Hua Deng, Duojia Pan, Xuelian Luo, and Xu Wu. 2016. “Autopalmitoylation of TEAD Proteins Regulates Transcriptional Output of Hippo Pathway.” Nature chemical biology 12 (4): 282-289. doi:10.1038/nchembio.2036. http://dx.doi.org/10.1038/nchembio.2036.1552-4450http://nrs.harvard.edu/urn-3:HUL.InstRepos:29002438TEA domain (TEAD) transcription factors bind to the co-activator YAP/TAZ, and regulate the transcriptional output of Hippo pathway, playing critical roles in organ size control and tumorigenesis. Protein S-palmitoylation attaches 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 is required for TEAD’s binding to YAP/TAZ, but dispensable for the binding to Vgll4 tumor suppressor. In addition, palmitoylation does not alter TEAD’s localization. Moreover, TEAD palmitoylation-deficient mutants impaired TAZ-mediated muscle differentiation in vitro, and Yorkie-mediated tissue overgrowth in Drosophila in vivo. Our study directly linked autopalmitoylation to the transcriptional regulation of Hippo pathway.en-USJournal Article2016-10-1110.1038/nchembio.2036