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bioRxiv · 10.1101/2022.12.12.520165

Regulation of RAS palmitoyltransferases by accessory proteins and palmitoylation

Yang, A.·Liu, S.·Zhang, Y.·Chen, J.·Feng, S.·Wu, J.·Hu, Q.
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Abstract

SummaryPalmitoylation of cysteine residues at the C-terminal hypervariable regions in human HRAS and NRAS, which is necessary for the RAS signaling, is catalyzed by the acyltransferase DHHC9 in complex with its accessory protein GCP16. The molecular basis for the acyltransferase activity and the regulation of DHHC9 by GCP16 is not clear. Here we report the cryo-EM structures of the human DHHC9-GCP16 complex and its yeast counterpart -- the Erf2-Erf4 complex, demonstrating that GCP16 and Erf4 are not directly involved in the catalytic process but stabilize the architecture of DHHC9 and Erf2, respectively. We found that a phospholipid binding to an arginine-rich region of DHHC9 and palmitoylation on three residues (C24, C25, and C288) were essential for the catalytic activity of the DHHC9-GCP16 complex. Furthermore, we showed that GCP16 also formed complexes with DHHC14 and 18 to catalyze RAS palmitoylation. These findings provide insights into the regulation mechanism of RAS palmitoyltransferases.

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Yang, A., Liu, S., Zhang, Y., Chen, J., Feng, S., Wu, J., Hu, Q.. 2022-12-13. Regulation of RAS palmitoyltransferases by accessory proteins and palmitoylation. https://doi.org/10.1101/2022.12.12.520165

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