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.

Source:
Journal reference:

Van den Boom, J., et al. (2021) Targeted substrate loop insertion by VCP/p97 during PP1 complex disassembly. Nature Structural & Molecular Biology. doi.org/10.1038/s41594-021-00684-5.

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