New mPROSS Algorithm Stabilizes Membrane Proteins, Enhancing Human CerS2's Stability

Researchers have developed a novel method, mPROSS, for efficiently stabilizing integral membrane proteins. This has been exemplified by successfully modifying human CerS2 for enhanced stability, leveraging AlphaFold2's structural predictions. The study, conducted by Iris D. Zelnik, Beatriz Mestre, and several others, was published on April 22, 2023.

The research introduces a new approach for stabilizing membrane proteins, which are critical components encoded by a substantial portion of the human genome. Traditional methods of stabilization involved repeated cycles of mutation and testing. However, this new strategy employs a unique algorithm named mPROSS that simplifies the process by using structural models from AlphaFold2. According to the study, this advancement allows for direct and efficient stabilization of these complex proteins, which are often difficult to analyze using standard techniques like X-ray crystallography or cryo-electron microscopy.

Zelnik and her team demonstrated the practical application of mPROSS on ceramide synthase (CerS2), a key enzyme in lipid production. By applying this algorithm, they were able to identify and implement 37 specific mutations that significantly increased the stability of human CerS2. The researchers say this is significant given that less than 2% of proteins in the Protein Data Bank are membrane proteins. The enhanced stability of CerS2 paves the way for deeper understanding and potential manipulation of lipid metabolism and transport processes.

In addition to stabilizing CerS2, the researchers also explored potential pathways for substrate delivery to ceramide synthases using molecular dynamics simulations. According to their findings, ceramide synthases play a vital role in mammals as they are responsible for the synthesis of ceramide - a crucial lipid for structural and signaling purposes. They highlighted the reliability of AlphaFold2's structural models for mutational analysis and design calculations as it offers a robust framework for future studies in the field of membrane protein research and lipid metabolism.