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What Chaperone Proteins Know

Here's a riddle for you: Proteins are used to make proteins, so if we assume a purely naturalistic origin of life, where did the first proteins come from?

If a cell is a factory, proteins are the factory workers. Proteins conduct most of the necessary functions in a cell. Proteins are made up of amino acid building blocks. A chain of amino acids must fold into the appropriate three-dimensional structure so that the protein can function properly. Within cells are proteins known as chaperones that help fold the amino acid chain into its proper three-dimensional structure. If the amino acid chain folds improperly, then this could wreak havoc on the cell and potentially the entire organism. The chaperone works to prevent folding defects and is a key player in the final steps of protein synthesis.

However, as important as chaperones are, there are still many questions as to how exactly they work. For example, do the chaperones fold the amino acid chain while it is still being constructed (during translation), or is the amino acid chain first put together, and then the folding beings? Or, is it some combination of both? Studies indicate that it is indeed a combination of both. There are two different kinds of chaperone proteins within the cell, one for translation and one for post-translation. With these two different kinds of chaperones, where and how does regulation happen to prevent misfolds?

Recent research on bacterial cells sheds light on the chaperones' important function. One chaperone in particular, Trigger Factor, plays a key role in correcting misfolds that may occur early on in the translational process. Trigger Factor can slow down improper amino acid folding, and it can even unfold amino acid chains that have already folded up incorrectly.

Here are some of the neat features of Trigger Factor:

  • Trigger Factor actually constrains protein folding more than the ribosome does. It doesn't just "get in the way" like the ribosome. It also regulates the folding.
  • Trigger Factor's function is specific to the particular region of the amino acid chain. It does not just perform one function no matter what the composition of the amino acid chain. It changes based on the region of the chain it is working with.
  • Trigger Factor also changes its activity based on where the protein is in the translation process.
  • Trigger Factor's process depends on how the amino acid chain is bound to the ribosome, and can even unfold parts of the chain that were misfolded in the translation process.

An additional factor that regulates when amino acid chains fold into proteins is its distance from the ribosome (the place where the amino acid chain is made). The closer the chain is to the ribosome, the less room it has to fold into a three-dimensional protein. Trigger Factor works with this spatial hindrance, making an interesting and complex regulation system.

Trigger Factor is only called into the game once the amino acid chain is a certain length (around 100 amino acids long) and when the chain has certain features, such as hydrophobicity. As the authors state it, Trigger Factor keeps the protein from folding into its three-dimensional structure until the amino acid chain has all of the information it needs to fold properly:

In summary, we show that the ribosome and TF each uniquely affect the folding landscape of nascent polypeptides to prevent or reverse early misfolds as long as important folding information is still missing and the nascent chain is not released from the ribosome.
So we have a protein that is able to perform various functions that inhibit or slow protein folding until the amino acid has the right chemical information for folding to occur.

This does not solve the riddle about proteins being made from proteins (otherwise known as the chicken-and-the-egg problem). It actually adds another twist to the riddle: How does one protein know how much information a completely different protein needs to fold into a three dimensional structure? How does a protein evolve the ability to "know" how to respond to specific translational circumstances as Trigger Factor does?