Structures of LRP2 reveal a molecular machine for endocytosis


Low-density lipoprotein (LDL) receptor-related protein 2 (LRP2), also known as megalin, is a protein found on the surface of many different types of cells in the body, including kidney cells, neurons, and epithelial cells in the lungs and gastrointestinal tract. LRP2 plays a critical role in several physiological processes, and its importance in medicine is becoming increasingly recognized.

LRP2 is thought to play important roles in physiology and disease. For instance LRP2 is highly expressed in the proximal tubules of the kidney, where it plays a crucial role in the reabsorption of important nutrients, including vitamin D, folate, and iron. LRP2 also helps to remove proteins and other molecules from the urine, preventing them from being excreted and conserving these valuable substances in the body. Moreover, LRP2 has been implicated in several neurological disorders, including Alzheimer’s disease, Parkinson’s disease, and multiple sclerosis. Studies have shown that LRP2 is involved in the clearance of beta-amyloid, a protein that accumulates in the brains of Alzheimer’s patients, as well as in the transport of lipids and other molecules that are critical for neuronal function. Furthermore, LRP2 is expressed in the epithelial cells of the lungs, where it plays a role in the clearance of surfactant, a substance that helps to keep the air sacs in the lungs from collapsing. Mutations in the LRP2 gene have been associated with a rare lung disease called congenital pulmonary alveolar proteinosis, which is characterized by the accumulation of surfactant in the lungs. It is also believed that LRP2 is overexpressed in several types of cancer, including breast, lung, and prostate cancer. Studies have shown that LRP2 plays a role in cancer cell proliferation, invasion, and metastasis, and that targeting LRP2 may be a promising therapeutic strategy for these types of cancer.

Overall, LRP2 is an important protein with diverse physiological roles, and its functions in different tissues are still being discovered. Its role in various diseases highlights its potential as a therapeutic target for the development of new treatments. Scientists at Columbia University have discovered how a large, life-sustaining protein known as megalin, or LRP2, works, revealing its role as a tiny ferry transporting molecular passengers across cell membranes in tissues and organs such as the kidneys, lungs, and brain. The breakthrough, detailed in the journal Cell, comes after a team of biochemists, nephrologists, and neuroscientists used cryogenic electron microscopy to produce 3D protein structures of the molecule in near-atomic detail. The researchers believe their work could lead to novel treatments for conditions such as acute kidney injury, chronic kidney disease, Alzheimer’s, and Donnai-Barrow syndrome.

Endocytosis is a vital cellular process that involves the uptake of extracellular material into cells. This process plays a critical role in many physiological functions, such as nutrient uptake, cell signaling, and the removal of cellular debris. However, dysregulation of endocytosis can contribute to the development of various diseases. For instance, endocytosis is essential for maintaining the balance between the production and degradation of signaling molecules, which is crucial for normal cell growth and division. Alterations in endocytosis can lead to the accumulation of growth factors and receptors, which can promote abnormal cell proliferation and cancer development. Moreover, endocytosis is involved in the regulation of synaptic transmission and the clearance of misfolded proteins from the extracellular space. Dysregulation of endocytosis can lead to the accumulation of toxic proteins in the brain, which is a hallmark of neurodegenerative diseases such as Alzheimer’s and Parkinson’s. Furthermore, endocytosis plays a critical role in the entry of many pathogens into host cells, including viruses, bacteria, and parasites. Pathogens can hijack the endocytic machinery to enter host cells and evade the immune system, leading to infection and disease.

In conclusion, endocytosis is a fundamental process that is critical for the proper functioning of cells and tissues. Dysregulation of endocytosis can contribute to the development of various diseases, highlighting the importance of understanding this process in the context of human health and disease. Detailed knowledge of LRP2 structure will pave the way for new therapeutic targets to treat many diseases.

Structures of LRP2 reveal - Medicine Innovates

About the author

Lawrence S. Shapiro, PhD

Professor of Biochemistry and Molecular Biophysics and Ophthalmic Science (in Ophthalmology and in the Naomi Berrie Diabetes Center); Principal Investigator at Columbia’s Zuckerman Institute.

Lawrence Shapiro uses structural information obtained from X-ray crystallography to direct biochemical studies of biological problems, particularly involving neuronal cell adhesion, cell-cell interactions, and neural patterning.


Beenken A, Cerutti G, Brasch J, Guo Y, Sheng Z, Erdjument-Bromage H, Aziz Z, Robbins-Juarez SY, Chavez EY, Ahlsen G, Katsamba PS, Neubert TA, Fitzpatrick AWP, Barasch J, Shapiro L. Structures of LRP2 reveal a molecular machine for endocytosis. Cell. 2023 Feb 16;186(4):821-836.e13. doi: 10.1016/j.cell.2023.01.016. Epub 2023 Feb 6. PMID: 36750096.