Research in Brief: The What, Why, and How

Elementary landscape model simulations

In this edition:

New research from the Raman Lab in the Department of Biochemistry decodes the evolutionary pathway of regulatory proteins. Here’s the run down on their recent research and paper, which is published in Cell Systems:

  • Proteins acquire and lose functions through evolutionary processes as cells adapt to changes in their environment over time.
  • Protein evolution is well studied in certain enzymes but is understudied in regulatory proteins, which help control gene expression.
  • A new, comprehensive study of the evolution of one regulatory protein reveals that how proteins evolve to gain and lose functions over time differs among classes of proteins. While some proteins evolve in a stepwise manner, others follow an evolutionary pattern which protects them from performing multiple functions simultaneously.

What background information do you need to know?

The finches of the Galápagos, famously described by Darwin, are often used as the quintessential example of evolution. Over time, naturally occurring genetic mutations led to small, incremental changes in the birds’ appearances. Changes that gave finches an advantage were passed on to subsequent generations, eventually resulting in a variety of beak and body shapes well-adapted to various diets and foraging techniques.

Biomolecules, too, evolve over time to acquire new functions and lose unnecessary ones in response to changes in a cell’s environment, such as exposure to new molecules or the introduction of pathogens. This evolution is an ongoing process which favors mutations that allow organisms to function effectively and efficiently.

For example, scientists know that enzymes — a class of proteins responsible for starting and speeding up biochemical reactions — evolve incrementally. Individual mutations accumulate, ultimately giving the enzyme a new or additional function in a cell.

But this pattern of evolution does not hold true for all classes of proteins.

Why do evolutionary patterns differ among proteins?

While some proteins can evolve incrementally to alter their functions, sometimes even performing multiple functions, regulatory proteins have a more delicate system to balance.

Regulatory proteins help to control gene expression, turning genes “on” and “off” like a light switch. If a single light switch controls the expression of multiple genes, it becomes harder to control expression of just one of the genes. This is why regulatory proteins typically have a limited set of functions: performing multiple, related functions may lead to catastrophic effects, including cell death, altered gene expression, or uncontrolled cellular division which can result in tumors. The stakes of mutating and evolving are higher when a protein’s function is so important and complex.

How have scientists made progress?

To better understand the evolutionary trajectory of regulatory proteins, researchers in the Raman Lab mapped the evolution over millennia of a specific kind of regulatory protein called a transcriptional regulator. This protein helps to control the rate at which RNA is synthesized from DNA.

Elementary landscape model simulations
Proteins evolve along fitness landscapes through mutations. Protein fitness landscapes have peaks and valleys, like geographical landscapes. Each panel represents a different fitness landscape of a transcription regulator family. The color shades within the small circles represents peaks and valleys. The lines connecting the circles represent mutational steps through the landscape i.e., “walking” through the landscape.

They extrapolated a probable history of the protein’s mutations using computer modeling. This approach gave them hundreds more DNA sequences representing the protein’s evolutionary history than have been used in past studies. Using this data, they tracked the protein’s likely mutations — and the resulting gain and loss of function — revealing a novel evolutionary pattern.

In contrast to the stepwise patterns seen in enzymes, transcriptional regulatory proteins rapidly gain or lose function when they acquire mutations. This rapid change helps them maintain their singular role of binding to specific molecules, preventing them from performing multiple roles simultaneously.

Raman and his team believe that the evolutionary pattern their study revealed in transcriptional regulators may be observed in other regulatory proteins, as well. Deeper understanding of the evolutionary landscape of transcriptional regulators will help scientists design new regulators to control gene circuits, sense molecules, engineer biosynthetic pathways, and monitor cellular metabolites, opening the door for new biomedical and biotechnological discoveries.

Written by Renata Solan. This research will appear on the cover of the April 17 issue of Cell Systems.

In Research In Brief: The What, Why, and How, we explore new research from the UW–Madison Department of Biochemistry to learn more about the world around us — and inside us.
This edition of Research in Brief: The What, Why, and How is based on the following publication:
Meger, Spence, Sandhu, Jackson, and Raman. Rugged fitness landscapes minimize promiscuity in the evolution of transcriptional repressors, Cell Systems, 2024 Mar 20, 1-16(31).
This research was funded in part by the NIH Director’s New Innovator Award DP2GM132682 and the Great Lakes Bioenergy Research Center, U.S. Department of Energy, Office of Science, Office of Biological and Environmental Research award number DE-SC0018409.