Scientists discover the evolutionary link between protein structure and function

Scientists discover the evolutionary link between protein structure and function
The two loops, shown in gold near the bottom of the protein structure, delimit the pocket where heme subunit resides and where oxygenation occurs. Credit: Gustavo Caetano-Anollés

Proteins are more than a dietary requirement. This diverse set of molecules powers nearly all of the cellular operations in a living organism. Scientists may know the structure of a protein or its function, but haven't always been able to link the two.

"The big problem in biology is the question of how a does what it does. We think the answer rests in protein evolution," says University of Illinois professor and bioinformatician Gustavo Caetano-Anollés.

Geologists have found remnants of life preserved in rock billions of years old. In some cases, preservation of microbes and tissues has been so good that microscopic cellular structures that were once associated with specific proteins, can be detected. This geological record gives scientists a hidden connection to the evolutionary history of protein structures over incredibly long time periods. But, until now, it hasn't always been possible to link function with those structures to know how proteins were behaving in cells billions of years ago, compared with today.

"For the first time, we have traced evolution onto a biological network," Caetano-Anollés notes.

Caetano-Anollés and graduate students Fayez Aziz and Kelsey Caetano-Anollés used networks to investigate the linkage between and molecular function. They built a timeline of protein structures spanning 3.8 billion years across the geological record, but needed a way to connect the structures with their functions. To do that, they looked at the genetic makeup of hundreds of organisms.

"It turns out that there are little snippets in our genes that are incredibly conserved over time," Caetano-Anollés says. "And not just in human genomes. When we look at higher organisms, such as plants, fungi and animals, as well as bacteria, archaea, and viruses, the same snippets are always there. We see them over and over again."

The research team found that these tiny gene segments tell proteins to produce "loops," which are the tiniest structural units in a protein. When loops come together, they create active sites, or molecular pockets, which give proteins their function. For example, hemoglobin, the protein that carries oxygen in blood, has two loops which create the active site that binds oxygen. The loops combine to create larger protein structures called domains.

Remarkably, the new study shows that loops have been repeatedly recruited to perform new functions and that the process has been active and ongoing since the beginning of life.

"This recruitment is important for understanding biological diversity," Caetano-Anollés says.

One important aspect of the study relates to the actual linkage between domain structure and functional loops. The researchers found that this linkage is characterized by an unanticipated property that unfolds in time, an "emergent" property known as hierarchical modularity.

"Loops are cohesive modules, as are domains, proteins, cells, organs, and bodies." Caetano-Anollés explains. "We are all made of cohesive modules, including our human bodies. That's hierarchical modularity: the building of small cohesive parts into larger and increasingly complex wholes."

Hierarchical modularity also exists in manmade networks, such as the internet. For example, each router represents a "node" that pushes information to different computers. When millions of computers interact with each other online, larger and more complex entities emerge. Caetano-Anollés suggests that the evolution of manmade networks could be mapped in the same way as the evolution of biological networks.

"From a computer science point of view, few people have been exploring how to track networks in time. Imagine exploring how the internet grows and changes when new routers are added, are disconnected, or network with each other. It's a daunting task because there are millions of routers to track and internet communication can be highly dynamic. In our study, we are showcasing how you can do it with a very small network," Caetano-Anollés explains.

The methods developed by Caetano-Anollés and his team now have the potential to explain how change is capable of structuring systems as varied as the internet, social networks, or the collective of all proteins in an organism.

Explore further

Study of giant viruses shakes up tree of life

More information: M. Fayez Aziz et al, The early history and emergence of molecular functions and modular scale-free network behavior, Scientific Reports (2016). DOI: 10.1038/srep25058
Journal information: Scientific Reports

Citation: Scientists discover the evolutionary link between protein structure and function (2016, May 18) retrieved 23 July 2019 from
This document is subject to copyright. Apart from any fair dealing for the purpose of private study or research, no part may be reproduced without the written permission. The content is provided for information purposes only.

Feedback to editors

User comments

you can almost palpate the researchers' excitement, bringing out the big guns- Borges and Leibniz :D

May 18, 2016
you can almost palpate the researchers' excitement, bringing out the big guns- Borges and Leibniz :D

Lucrecia? D~

May 19, 2016
"From a computer science point of view, few people have been exploring how to track networks in time."

Isn't that Cisco's business model and reason for existence? This is what Network Administrators do!

May 19, 2016
Reminds me of a recent article on here regarding a new catalyst to turn alkanes into valuable pharmaceuticals. IT too utilised a ring/spherical structure to limit (select) access to the reactive sites hidden inside. It also provided handedness specificity. Seems we might be at the dawn of a catalyst chemist dream era. Once we understand natures catalysts, expect the chemistry sector to boom.

May 20, 2016
Caetano-Anollés is known for his team's prodigious output of enormously detailed protein phylogenies forming the basis of this and that. He has the biology and computer chops. But no one has ever tried to verify any of it to my knowledge. You imagine the peer reviewers crossing their fingers and hope the computer models work as advertised, and go on to criticize other stuff.

Which makes me think that he is considered to be a fringe worker. I haven't seen anyone base further work on his. But I don't know.

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more