Biologists discover how a protein works in our body

It’s an old hand knitting trick, and a protein in our bodies knows it: instead of threading the yarn from the end into the eye, it can be easier to put a loop through it. This is how a protein works in our body by unfolding or separating other protein structures. Biologists from the University of Duisburg-Essen (UDE) made this discovery and published it in Nature Structural & Molecular Biology.

Proteins are both: building blocks and tools of our cells and each consist of a long thread of amino acids. Only when this thread is folded into a ball in a certain way can a protein function.

Sometimes this three-dimensional structure has to be disentangled again – especially when proteins are broken down. To do this, the long amino acid thread is threaded through a kind of funnel, loses its ball shape and separates from the partner protein. The funnel is itself a protein called VCP / p97 that other proteins can suck in through its central pore. Important for the cell’s own quality control: If a protein is incorrectly folded, it is disentangled by VCP / p97 and then broken down.

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

Johannes van den Boom from Molecular Biology I, first author

To do this, the team used a protein engineering trick for the structures, which were only a few millionths of a millimeter in size: They seamlessly connected the two ends of the amino acid strand to be unfolded, thus forming a ring. And indeed – the two proteins examined were nevertheless separated from one another.

“Now we know that VCP / p97 can not only unfold proteins but also separate them from one another and that its pore is even large and flexible enough to accommodate the double-layered amino acid strand in a loop,” summarizes van den Boom.

Such basic research is essential in order to understand cellular mechanisms in detail and, based on this, to better understand processes such as those involved in neurodegenerative diseases.


Journal reference:

van den Boom, J., et al. (2021) Targeted substrate loop insertion by VCP / p97 during PP1 complex breakdown. Nature structural and molecular biology.

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