Computational design and molecular dynamics simulations suggest the mode of substrate binding in ceramide synthases

Iris D Zelnik; Beatriz Mestre; Jonathan J Weinstein; Tamir Dingjan; Stav Izrailov; Shifra Ben-Dor; Sarel J Fleishman; Anthony H Futerman

doi:10.1038/s41467-023-38047-x

Computational design and molecular dynamics simulations suggest the mode of substrate binding in ceramide synthases

Iris D Zelnik, Beatriz Mestre, Jonathan J Weinstein, Tamir Dingjan, Stav Izrailov, Shifra Ben-Dor, Sarel J Fleishman, Anthony H Futerman

Weizmann Institute of Science

Research output: Contribution to journal › Article › peer-review

Abstract

Until now, membrane-protein stabilization has relied on iterations of mutations and screening. We now validate a one-step algorithm, mPROSS, for stabilizing membrane proteins directly from an AlphaFold2 model structure. Applied to the lipid-generating enzyme, ceramide synthase, 37 designed mutations lead to a more stable form of human CerS2. Together with molecular dynamics simulations, we propose a pathway by which substrates might be delivered to the ceramide synthases.

Original language	English
Article number	2330
Journal	Nature Communications
Volume	14
Issue number	1
DOIs	https://doi.org/10.1038/s41467-023-38047-x
State	Published - Dec 2023

All Science Journal Classification (ASJC) codes

General Chemistry
General Biochemistry,Genetics and Molecular Biology
General Physics and Astronomy

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10.1038/s41467-023-38047-xLicense: CC BY

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abstract = "Until now, membrane-protein stabilization has relied on iterations of mutations and screening. We now validate a one-step algorithm, mPROSS, for stabilizing membrane proteins directly from an AlphaFold2 model structure. Applied to the lipid-generating enzyme, ceramide synthase, 37 designed mutations lead to a more stable form of human CerS2. Together with molecular dynamics simulations, we propose a pathway by which substrates might be delivered to the ceramide synthases.",

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AU - Dingjan, Tamir

AU - Izrailov, Stav

AU - Ben-Dor, Shifra

AU - Fleishman, Sarel J

AU - Futerman, Anthony H

PY - 2023/12

Y1 - 2023/12

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AB - Until now, membrane-protein stabilization has relied on iterations of mutations and screening. We now validate a one-step algorithm, mPROSS, for stabilizing membrane proteins directly from an AlphaFold2 model structure. Applied to the lipid-generating enzyme, ceramide synthase, 37 designed mutations lead to a more stable form of human CerS2. Together with molecular dynamics simulations, we propose a pathway by which substrates might be delivered to the ceramide synthases.

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Computational design and molecular dynamics simulations suggest the mode of substrate binding in ceramide synthases

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