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Cell Research

Cell Research

IF: 25.9
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Cholesterylation of Smoothened is a calcium-accelerated autoreaction involving an intramolecular ester intermediate

Published:4 February 2022 DOI: 10.1038/s41422-022-00622-0 PMID: 35121857
Ao Hu, Jing-Zan Zhang, Jie Wang, Chen-Chen Li, Meng Yuan, Gang Deng, Zi-Cun Lin, Zhi-Ping Qiu, Hu-Yue Liu, Xian-Wei Wang, Peng-Cheng Wei, Xiao He, Xiaolu Zhao, Wen-Wei Qiu, Bao-Liang Song

Abstract

Hedgehog (Hh) is a morphogen that binds to its receptor Patched 1 and activates Smoothened (SMO), thereby governing embryonic development and postnatal tissue homeostasis. Cholesterol can bind and covalently conjugate to the luminal cysteine-rich domain (CRD) of human SMO at the D95 residue (D99 in mouse). The reaction mechanism and biological function of SMO cholesterylation have not been elucidated. Here, we show that the SMO-CRD undergoes auto-cholesterylation which is boosted by calcium and involves an intramolecular ester intermediate. In cells, Hh stimulation elevates local calcium concentration in the SMO-localized endosomes through store-operated calcium entry. In addition, we identify the signaling-incompetent SMO D95E mutation, and the D95E mutant SMO can bind cholesterol but cannot be modified or activated by cholesterol. The homozygous SmoD99E/D99E knockin mice are embryonic lethal with severe developmental delay, demonstrating that cholesterylation of CRD is required for full-length SMO activation. Our work reveals the unique autocatalytic mechanism of SMO cholesterylation and an unprecedented role of calcium in Hh signaling.

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Rapamycin 53123-88-9 C51H79NO13 1033 suppliers $9.00-$6160.00
Rapamycin 53123-88-9 C51H79NO13 1033 suppliers $9.00-$6160.00
Rapamycin 53123-88-9 C51H79NO13 1033 suppliers $9.00-$6160.00
Rapamycin 53123-88-9 C51H79NO13 1033 suppliers $9.00-$6160.00
Vismodegib 879085-55-9 C19H14Cl2N2O3S 281 suppliers $8.00-$1802.00
Vismodegib 879085-55-9 C19H14Cl2N2O3S 281 suppliers $8.00-$1802.00
Vismodegib 879085-55-9 C19H14Cl2N2O3S 281 suppliers $8.00-$1802.00
Vismodegib 879085-55-9 C19H14Cl2N2O3S 281 suppliers $8.00-$1802.00
Rapamycin 53123-88-9 - Inquiry
Rapamycin 53123-88-9 - Inquiry

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