Scientists created 3D maps to treat kidney and brain diseases better
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A. Fitzpatrick, A Beenken, L. Shapiro / Columbia's Zuckerman Institute.
Nephrologists and neuroscientists collaborated at Columbia University to develop 3D maps of proteins and how they aid the organs' ability to filter toxins.
Along with colleagues from other institutions, they revealed for the first time a picture of a protein that can make or break a person's life that is clear enough to explain how it functions: as a tiny ferry for molecules that must pass through nearly a trillion cell membranes in tissues and organs ranging from kidneys and brains to the inner ear and the lungs' alveoli, according to Columbia University Zuckerman Institute.
"With new mechanistic understanding of this key protein and how mutations in it can shut it down, we are hoping that follow-on research will uncover novel targets for treating kidney and brain diseases," said Jonathan Barasch, MD, Ph.D., an expert and clinician in urology and nephrology at Columbia's Vagelos College of Physicians and Surgeons and a corresponding author on the paper.
"These new therapeutic openings are due to the amazing protein structures my Columbia colleagues Andrew Beenken, Anthony Fitzpatrick, and Larry Shapiro have uncovered," he added.
It may treat several diseases
The new high-resolution protein structures could provide therapeutic leads for treating conditions as common as acute kidney injury, chronic kidney disease, and Alzheimer's disease, as well as those that are uncommon, like Donnai-Barrow syndrome, a genetic disorder with a variety of physical and mental consequences.
With the help of Dr. Beenken's arduously acquired LRP2 samples, co-corresponding author Dr. Anthony Fitzpatrick and Beenken gathered a large amount of structural data. The researchers then created 3D protein structures with nearly atomic detail, skillfully utilizing robust computational methods to make sense of the data.
"We now have the best 3D maps of the LRP2 protein ever created," said Dr. Fitzpatrick, 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. With those maps, Dr. Shapiro could begin to tease out the remarkable mechanism by which LRP2 works in cells.
The study was published in Cell on February 6.
Study abstract
The low-density lipoprotein (LDL) receptor-related protein 2 (LRP2 or megalin) is representative of the phylogenetically conserved subfamily of giant LDL receptor-related proteins, which function in endocytosis and are implicated in diseases of the kidney and brain. Here, we report high-resolution cryoelectron microscopy structures of LRP2 isolated from mouse kidney, at extracellular and endosomal pH. The structures reveal LRP2 to be a molecular machine that adopts a conformation for ligand binding at the cell surface and for ligand shedding in the endosome. LRP2 forms a homodimer, the conformational transformation of which is governed by pH-sensitive sites at both homodimer and intra-protomer interfaces. A subset of LRP2 deleterious missense variants in humans appears to impair homodimer assembly. These observations lay the foundation for further understanding the function and mechanism of LDL receptors and implicate homodimerization as a conserved feature of the LRP receptor subfamily.
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