New understanding of protein processing could have implications for Alzheimer's and some cancers

Originally published by Katherine Fenz, Rockefeller University, on Jun 5, 2025

edited by Lisa Lock, reviewed by Andrew Zinin

Three dimensional cryo-EM structure of VCP (blue and purple) bound to three VCPIP1 promoters (red, orange, and yellow). Credit: Kapoor lab

Healthy cells are constantly breaking down proteins and building up new ones with the help of enzymes aptly named unfoldases, because they unravel proteins tagged for destruction or recycling. Now, a new electron microscopy study demonstrates how VCP, one such unfoldase, physically interacts with tag removal enzymes, called DUBs.

The findings show how these two enzymes work in tandem to process proteins, and may have implications for the study of diseases such as those linked to neurodegeneration. The research is published in the Journal of Cell Biology.

"VCP dysfunction is linked to neurodegenerative disorders, such as Alzheimer's," says first author Lauren Vostal, a graduate student in the laboratory of Tarun Kapoor and now a senior scientist at Boehringer Ingelheim. "Actually being able to see physical contact between VCP and DUBs can provide insight into how these two enzymes are coordinated to regulate protein degradation."

Unfolding and cutting

Cells maintain proteostasis—a careful balance of the number of proteins present—through a series of coordinated mechanisms that ensure the rates of synthesis and degradation remain in concert. Because certain proteins cannot be degraded until they are first unfolded, unfoldases like VCP play a crucial role in this system.

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