Researchers find that the VCP/p97 protein unfolds, separates other protein structures

Thanks to an old needlework trick that a protein in the human body is aware of, rather than threading yarn into the eye from the end, it could be simpler to pass a loop through it.

This is the way a protein in the human body works by unfolding or isolating other protein structures. This discovery was achieved by biologists from the University of Duisburg-Essen (UDE), who have reported it in Nature Structural & Molecular Biology.

Proteins are not just the building blocks and the tools of human cells, they also contain a long thread of amino acids. A protein can perform its functions only when this thread folds into a clew in a specific way.

At times, this three-dimensional structure must be untangled again—specifically during the degradation of proteins. This is achieved by threading the long thread of amino acids through a kind of funnel, where the thread loses its tangled shape and gets isolated from the partner protein.

The funnel is itself a protein named VCP/p97, which can draw in other proteins via its central pore. It plays a major role in the cell’s own quality control: in case a protein gets misfolded, it is untangled through VCP/p97 for further degradation.

We were able to demonstrate that in at least one case, threading into the pore of VCP/p97 does not happen from the ends, as we initially suspected. Instead, it starts in the middle of the protein strand, where a specific sequence of amino acids is recognized.”

Johannes van den Boom, Study First Author, Molecular Biology I, University of Duisburg-Essen

The researchers achieved this by using a protein designing trick for the structures, which are sized at only a few millionths of a millimeter: They smoothly linked the two ends of the amino acid strand to be unfolded, thus making a ring. In fact, the two analyzed proteins were however isolated from each other.

Now we know that VCP/p97 can not only unfold proteins, but also separate them from each other, and its pore is even large and flexible enough to accommodate the double-laid amino acid strand in the loop.”

Johannes van den Boom, Study First Author, Molecular Biology I, University of Duisburg-Essen

Basic studies of this type are crucial to gain insights into the cellular mechanisms in detail and, using this, to better perceive processes like those involved in neurodegenerative diseases.