Cell complexity: molecular binding controls (Introduction)

by David Turell , Tuesday, January 25, 2022, 20:28 (1034 days ago) @ David Turell

Among the myriad of molecules in a cell, how do they know how tov whom they should bind:

https://phys.org/news/2022-01-probing-proteins-pair-cells.html

"Despite its minute size, a single cell contains billions of molecules that bustle around and bind to one another, carrying out vital functions. The human genome encodes about 20,000 proteins, most of which interact with partner proteins to mediate upwards of 400,000 distinct interactions. These partners don't just latch onto one another haphazardly; they only bind to very specific companions that they must recognize inside the crowded cell.

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"The average human protein is composed of approximately 400 building blocks called amino acids, which are strung together and folded into a complex 3D structure. Within this long string of building blocks, some proteins contain stretches of 4-6 amino acids called short linear motifs (SLiMs), which mediate protein-protein interactions. Despite their simplicity and small size, SLiMs and their binding partners facilitate key cellular processes. However, it's been historically difficult to devise experiments to probe how SLiMs recognize their specific binding partners.

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"Using the detailed information they gleaned from studying these interactions, the researchers created their own synthetic molecule capable of binding extremely tightly to a protein called ENAH, which is implicated in cancer metastasis. The team shared their findings in a pair of eLife studies, one published on January 25, 2022 and the other on December 2, 2021.

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"To survey SLiMs with a wide range of binding affinities, Keating, Hwang, and their colleagues developed their own screen called MassTitr.

"The researchers also suspected that the amino acids on either side of the SLiM's core 4-6 amino acid sequence might play an underappreciated role in binding. To test their theory, they used MassTitr to screen the human proteome in longer chunks comprised of 36 amino acids, in order to see which "extended" SLiMs would associate with the protein ENAH.

"ENAH, sometimes referred to as Mena, helps cells to move. This ability to migrate is critical for healthy cells, but cancer cells can coopt it to spread. Scientists have found that reducing the amount of ENAH decreases the cancer cells's ability to invade other tissues—suggesting that formulating drugs to disrupt this protein and its interactions could treat cancer.

"Thanks to MassTitr, the team identified 33 SLiM-containing proteins that bound to ENAH—19 of which are potentially novel binding partners. They also discovered three distinct patterns of amino acids flanking core SLiM sequences that helped the SLiMs bind even tighter to ENAH. Of these extended SLiMs, one found in a protein called PCARE bound to ENAH with the highest known affinity of any SLiM to date.

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"Hwang's biggest takeaway from the project is that things are not always as they seem: even short, simple protein segments can play complex roles in the cell. As she puts it: "We should really appreciate SLiMs more."

Comment: this study shows how molecules know with whom to combine or react, automatically, no thought involved because of the design. Cell intelligence is in the design, not autonomously
active.