Biochemical controls: more on disordered proteins (Introduction)

by David Turell , Saturday, September 21, 2024, 18:07 (61 days ago) @ David Turell

Another review article:

https://www.the-scientist.com/the-dynamic-lives-of-intrinsically-disordered-proteins-72...

"Today, scientists are hunting down a different kind of shape-shifting entity in search of answers about the inner workings of cellular life: intrinsically disordered proteins. Unlike their well-known, folded counterparts, intrinsically disordered proteins lack a single, stable three-dimensional structure. Instead they take on many different conformations.

"These dynamic, ever-changing proteins have long fallen through the cracks of conventional structural biology methods and have been excluded or ignored for their staunch defiance of a central tenet in protein science: structure defines function. However, a growing body of evidence found that these are not rare proteins performing odd jobs in the underbelly of our cells nor are they evolutionary junk hoarded in the proteome. They are well-known entities that are deeply entrenched in regulatory biology. Yet, scientists still know very little about the dynamic and disordered lives of these proteins that help keep the lights on in our cells.

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"Proteins drive essential biological processes in the body. From the enzymes that fuel chemical reactions to the antibodies enlisted by the immune system, these tiny molecular machines receive, integrate, and transmit cellular information. In the postgenomic era, scientists are working tirelessly to decipher the functions of the protein sequences encoded in the genome. Fueling these efforts is a central philosophy in biology that an amino acid sequence begets structure begets function; like a hammer’s head is designed to hit nails while its claw perfectly clasps onto nails to remove them, a protein’s three-dimensional structure is designed to interact with specific components in the cell to perform a specialized function. But what if a protein lacks a fixed structure?

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"Rather than pigeonholing proteins into either ordered and structured or disordered and unstructured, disorder is better viewed as a continuum. Some proteins have well defined structures with tiny, flexible disordered tails while others are entirely disordered, wiggly strands of amino acids. In a sequence, intrinsically disordered regions (IDR) range anywhere from short (five to 10 residue) snippets to long (1,000 or more) stretches of amino acids. A single protein can display several distinct IDR. It is estimated that around 30 to 40 percent of eukaryotic proteins harbor some degree of disorder.

"Proteins with disorder aren’t relegated to the sidelines of cellular activity. On the contrary, disordered proteins are stalwarts of cellular communication. “They have so many different functions. It’s incredible,” said Heller. Their conformational freedom facilitates a kind of functional promiscuity that provides cells with multiplexed and flexible recognition and response systems.5,6 In line with this, these malleable machines are often hubs for essential cellular processes, including gene regulation, cell division, molecular recognition, and cell signaling.

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"Folded proteins are not exactly frozen statues either; they are also wiggling and moving around the cell. “For disordered regions, that wiggling is just much more pronounced and there is no single reference state that is convenient to talk about or think about,” said Holehouse. He added that a more accurate framework for ordered and disordered proteins alike is a sequence-ensemble-function paradigm where ensemble denotes the collection of states that a protein exists in.

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"...a paradigm shift in how scientists think about protein interactions whereby an intrinsically disordered protein has an ensemble of possible conformations that allows the protein to respond to the environment and drive different functions accordingly.

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"Scientists are far from understanding disorder-based biology, but they hope that a growing awareness of their prevalence and importance alongside new tools will help uncover how disordered regions mediate cellular function and contribute to disease. These efforts have catapulted disordered proteins from a niche curiosity of biophysicists to entities that are increasingly accepted and appreciated for their regulatory roles in cellular function."

Comment: Like the previous entry this demonstrates how close to chaos are the functioning proteins in every cell. The only conclusion I can reach is that this is the only way life can exist. It is an error prone system, which gives rise to dhw's theodicy complaints about God: God should have developed life without these problems. He didn't because He knew this had to be the only way to create life.