Advanced Microscopy Techniques Help Map Out Protein Structure

A new scientific discovery has revealed the balance between health and disease at the atomic level of proteins. The findings were published in the journal Cell by a collaboration of nephrologists and neuroscientists at Columbia University. The study reveals, for the first time, the role of the protein LRP2 as a tiny “ferry” for molecular passengers that must cross nearly a trillion cell membranes in various organs and tissues.

The researchers hope the new high-resolution protein structures will lead to treatments for diseases such as acute kidney injury, chronic kidney disease, Alzheimer’s disease, and rare genetic disorders.

LRP2, a member of the LRP protein family, is crucial for recovering reusable molecules from filtered metabolic waste in kidney cells. It is distributed on the surface of cells and is essential for avoiding the expenditure of energy and resources in making reusable molecules again. The study’s authors hope that the new understanding of the protein and its mutations will lead to new targets for treating kidney and brain diseases.

The study’s first author, Andrew Beenken, MD, Ph.D., a biochemist and nephrologist at Columbia, harvested enough LRP2 protein from 500 mouse kidneys to analyze it with advanced microscopy techniques. Using a cryogenic electron microscope, the researchers collected vast amounts of structural data and produced 3D protein structures in near-atomic detail.

“We now have the best 3D maps of the LRP2 protein ever created,” said Anthony Fitzpatrick, Ph.D., a principal investigator at the Zuckerman Institute and an assistant professor of biochemistry and molecular biophysics at Columbia’s Vagelos College of Physicians and Surgeons. These maps will be crucial in deciphering LRP2’s ferrying mechanism and provide a basis for follow-up research to uncover novel targets for treating diseases.

The discovery of the role of LRP2 as a molecular ferry has been described as a “biochemical tour de force” and a “giant research step” in the field. With the creation of the best 3D maps of the protein to date, the researchers have opened new therapeutic opportunities for various diseases.

These findings highlight the value that can emerge from uncommon alliances in scientific research and the importance of studying proteins at the atomic level for understanding the balance between health and disease.