Yan Ning and other latest achievements: AI helps resolve the mystery of cholesterol metabolism

Yan Ning and other latest achievements: AI helps resolve the mystery of cholesterol metabolism

Yan Ning and other latest achievements: AI helps to analyze the mystery of cholesterol metabolism Yan Ning and other latest achievements: AI helps to analyze the mystery of cholesterol metabolism

On June 29, Beijing time, Professor Yan Ning of Princeton University, Assistant Professor Yan Chuangye Research Group of Tsinghua University, and Dr.
Yan Renhong of West Lake University jointly published a new research result in "Cell Report", further revealing the key to cholesterol metabolism Regulation mechanism
.

"This work has two highlights: the first is to use AI technology to assist in the analysis of low- and medium-resolution structures, and the second is to further understand the working mechanism of Scap protein and Insig protein as intracellular cholesterol sensors
.

" Yan Ning told " China Science Daily

How does the human body maintain cholesterol homeostasis through a negative feedback regulation mechanism? This is a very classic scientific problem
.

Joseph Goldstein and Michael Brown, winners of the Nobel Prize in Physiology or Medicine, played a very important role in the regulation of cholesterol metabolism, the SREBP (Sterol Regulatory Element-Binding Protein) signaling pathway identified in the 1990s

Scap and Insig are two key proteins in the SREBP pathway.
The interaction between them mediated by cholesterol molecules or cholesterol derivatives can regulate the activity of SREBP transcription factors and activate their uptake and synthesis when the intracellular cholesterol content is reduced.
Gene expression, and inhibit this process when the content increases, so as to achieve a negative feedback regulation mode
.

Due to the high technical difficulty, the structural biology research progress of this pathway has been relatively slow

Yan Ning once said with a smile that the SREBP pathway is her "first love topic": In 2001, she first went to Professor Shi Yigong's laboratory to study for a Ph.
D.
The first topic was the structural biology and biochemistry research on the SREBP pathway; she did it in 2005 The first topic of the postdoctoral fellow was the membrane protein in the SREBP pathway; the first 973 project of the Ministry of Science and Technology after the independent lead laboratory of Tsinghua University was also the structural biology research on the SREBP pathway
.

In January 2021, Yan Ning, Yan Chuangye, Yan Renhong and others published an important study in Science, and obtained the first electron microscope of human Scap and Insig-2 protein complex with an average resolution of about 3.
7 angstroms in the transmembrane region.
The structure is so clear that the details of the interaction between molecules can be directly observed
.

They also saw for the first time the important function of the molecule 25-hydroxycholesterol (25HC) on the interface of Scap and Insig-2 interaction, subverting the previous understanding of the binding site and regulation mechanism of 25HC

The paper published this time is a continuation of the previous paper
.

"Previous studies reported that there are two ways of interaction between Scap and Insig, one is mediated by 25HC, and the other is mediated by cholesterol binding to loop1 in the extracellular soluble region

The researchers further optimized the Scap and Insig composite samples through detergent screening, and were able to obtain low- and medium-resolution density maps of Scap's loop1 and loop7, but it was not enough to build its atomic model
.

How to do structural analysis with relatively low resolution images? The researchers used the AI ​​tool "tFold" developed by Tencent to predict the structure of the Scap protein in the extracellular region, and combined with a lower resolution electron density map to build the final structural model

There is another unexpected result of this study: The researchers used a detergent called "digitonin" to extract proteins from the cell membrane, but for the first time they found that this substance can be structurally specific.
Replace 25HC, promote the interaction between Scap and Insig
.

This may provide a potential target for the development of new drugs regulating cholesterol

"Cholesterol metabolism is closely related to one of the main killers of human health-cardiovascular and cerebrovascular diseases
.

In-depth exploration of the molecular mechanism of the SREBP pathway can deepen our understanding of cholesterol regulation, and help target the development of lipid-lowering drugs to improve cardiovascular and cerebrovascular diseases .

Link to the paper: https://doi.
org/10.
1016/j.
celrep.
2021.
109299