Cryo-EM maps how p97 and its partner proteins coordinate protein disposal

Researchers at the University of Münster, working with colleagues at the University of Duisburg-Essen, have visualised how the protein machine p97 cooperates with three partner proteins, Ufd1, Npl4 and FAF1, as it handles a target protein. Their structures suggest that the components continually adjust to one another during processing, rather than acting as independent parts. The work appears in Nature Communications.

A machine at the centre of protein quality control

p97 belongs to the AAA family of proteins, which use energy released from ATP to exert mechanical force on other proteins, moving them or changing their shape. In cells, p97 helps to prepare faulty or surplus proteins for breakdown and recycling. It can extract proteins from larger molecular assemblies and from membranes, which makes it important for maintaining the balance of the cell's protein content.

Faults in p97 itself have been linked to neurodegenerative diseases, multisystem disorders and cancer. Understanding the mechanism is therefore relevant to basic cell biology and to the study of several disease areas.

Why the partners matter

It has long been known that p97 rarely works alone. A large set of adapter proteins steers it towards particular tasks. How these adapters and p97 interact in detail while a substrate is being processed, however, has remained unclear. This is the gap the Münster team set out to address, led by Christos Gatsogiannis of the Institute of Medical Physics and Biophysics, with Athina Drakonaki as lead author.

Combining biochemistry with cryo-electron microscopy

The researchers paired biochemical experiments with cryo-electron microscopy, a technique that images frozen protein complexes and can resolve different molecular states in a sample. Using it, they captured several distinct arrangements of the p97-Ufd1-Npl4-FAF1 assembly at near-atomic resolution. From the range of arrangements, they inferred how the components coordinate their conformations in a dynamic interplay.

The results indicate that efficient handling of a defective protein depends on the combined activity of p97 and its adapters. As p97 acts mechanically on the substrate, its own structure changes. The adapters respond flexibly to help keep the process stable:

• Ufd1 and Npl4 shift their positions within the complex.
• FAF1 alters its distance from the complex according to need.

The team compares this interdependence to a coordinated dance, in which each participant complements the others while the substrate is processed.

Limits and next steps

The study is a structural and mechanistic investigation of one particular combination of adapters. p97 interacts with many others, and it remains open whether they behave in the same way. Gatsogiannis says the findings form a basis for examining how p97 works with further accessory proteins, and the group is already planning follow-up work.

The researchers also say that a better grasp of this mechanism could, in the longer term, inform targeted cancer therapies and treatments for neurodegenerative conditions. That is a prospect rather than a result: the paper reports no therapeutic testing, and any translation would depend on further work on how p97 and its partners function in different cellular contexts.

Relevance for researchers

For structural biologists and those studying protein homeostasis, the work offers a detailed picture of conformational coupling in a multi-component AAA machine. It also illustrates how cryo-electron microscopy can resolve several functional states of a flexible complex. Such structural data could serve as a reference for interpreting p97 mutations associated with disease and for designing experiments on other adapter combinations.

The study is titled "Structural dynamics of substrate processing by the p97-Ufd1-Npl4-FAF1 machinery" (DOI: 10.1038/s41467-026-78639-x).

Source: Molecular choreography: How the p97 protein regulates cellular quality control (Phys.org, 5 November 2026).

Image: AI-generated illustration.