An essential nutrient and fuel, proteins are considered the building block of life and are found in every cell of the body. Proteins are compound molecules of varying sizes made up of amino acids that play many critical roles in the body; most of which they achieve from within our cells where they regulate, build and support the body’s tissues and organs. Functions they fulfill in cells include antibodies, hormones, enzymes, and structural components.
Proteins achieve this multitude of functions in the body by folding into specific 3-D shapes that interact with different biomolecular structures, with general theory stating proteins require these fixed shapes to function.
Recently a new class of intrinsically disordered proteins (IDPs) have been discovered which consist of large regions that are ‘floppy’ or undefined, meaning they do not fold into a delineated static 3-D shape.
Using a new class of proteins
These IDPs have been shown to express bulky malleable regions that shift between an indissoluble and firm state, known as phase separation, allowing these domains to play a vital role in controlling various cellular functions. However, little is known about the control and inner-workings of these latterly discovered proteins.
Now, a study from researchers at Duke University demonstrates a method for controlling the phase separation of the emerging class of proteins, IDPs, to create artificial membrane-less organelles within human cells. The team states their major advance establishes a favorable environment for the inception of astrobiologics capable of modulating existing cell functions or spawning entirely new cellular functions. The study is published in the journal Nature Chemistry.
Previous studies show IDPs undergo what is known as phase transitions where they change from a liquid to a gel in response to environmental triggers, for instance, a change in temperature. Specifically, when IDPs are contained within cell walls, the cellular environment can regulate their phase transition state and functionality, as well as their molecular weight or amino acid sequence.
It has been posited this changeable intracellular control would proffer the promise of untold new classes of therapeutics if it could be harnessed, but it has been difficult to ascertain the rules governing this phase behavior.
Controlling intracellular functions
Earlier studies from the group identified IDPs that spontaneously form biomolecular condensates or organelles within cells. These are structures that allow cells to create compartments without building a membrane to encapsulate it. The current study engineers a biomimetic version of these organelle IDPs retaining the same phase behavior, that can be precisely tuned for a single functionality.
The current study alters the molecular weight and amino acid sequence of the artificial IDP, tweaking the two variables to enable the formation of organelle compartments at different temperatures in a test tube. This synthetic organelle was then trialed within E. coli, where the artificial IDPs were shown to successfully consolidate to form a tiny droplet within the cell’s cytoplasm.
As a keen understanding of how to manipulate the size and composition of the IDPs to respond to temperature was gained, the IDPs were then programmed to form droplets or compartments of varying densities within cells.
The lab states specifically, they wanted to engineer an organelle with the ability to perform a specific function within a cell, namely, using the IDPs to encapsulate an enzyme to control its activity. They selected an enzyme used by E. coli to convert lactose into sugars, tracking the enzyme’s activity to evidence how the artificial IDP organelle was modifying enzymatic reactions.
Results show by varying the molecular weight of the synthetic organelles, the biomimetic IDPs influence over the enzyme either increased or decreased, which in turn dictated its level of interaction with the rest of the cell.
Nextgen synthetic biology
The team surmises they have developed a new field of functional synthetic biology involving the precise control of cellular behavior using a recently discovered class of proteins. For the future, the researchers state they can see their biomimetic IDP organelles being used to investigate why their natural counterparts sometimes malfunction, and how to control this aberration and its associated diseases.
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