Nucleolus evolution: Scientists discover key role of TCOF1 protein

Credit: Pixabay/CC0 Public Domain

How did the nucleolus evolve? Scientists have some answers

In all living cells, biomolecular condensates that form loosely together do many important things. However, it is unclear how proteins and other biomolecules assemble in cells to form these communities. MIT biologists have discovered that one of the arena materials is responsible for forming one of the condensates that form in an organelle called the nucleolus. Condensate cannot form without this protein called TCOF1. 

These discoveries may assist analyze a major change in the way nucleolus are positioned about 300 million years ago. By then, the nucleolus (its role is to help build ribosomes) has split into two parts. However, in amniotes (including reptiles, birds, and mammals), the nucleolus forms a condensate that acts as a third. Biologists still do not understand why this change occurred.

"If you look at the tree of life, the structure and function of the ribosome remains the same, but the process of making it evolves. Different biochemicals come in that regulate ribosomes," said Eliezer Calo, a biology professor and senior author at MIT.

Scientists can more readily research the role of this condensation, known as the fibrous center, given that they are aware of how it develops. The findings also provide insight into how other condensates initially developed in the cells, the researchers said.

Former MIT graduate students Nima Jaberi-Lashkari Ph.D. and Byron Lee Ph.D. are the paper's principal authors, which appears in Cell Reports. Fardin Aryan, The paper's co-author is a former researcher at the Massachusetts Institute of Technology.

Condensate formation

Many cell functions are carried out by membrane-bound organelles, such as lysosomes and mitochondria, but membrane-less condensates also perform critical tasks such as gene regulation and stress response. Sometimes, condensation forms when needed and dissolves when the job is done.

"Almost every cellular function required for cell function is somehow related to condensate formation and function," Calo says. "However, how these condensates form is not fully resolved."

Calo and colleagues found a portion of the protein that appears to be involved in condensation formation in a 2022 investigation. The researchers employed computational tools to identify and compare low complexity regions (LCRs) from different species in this study. LCRs are a sequence of amino acids that are repeated many times with interspersed other amino acids.

This study also shows that a nucleolar protein called TCOF1 has many glutamate-rich LCRs that help build biomolecular components. In the new study, the researchers found that the form intensifies when TCOF1 is expressed in cells. Normal condensates contain proteins normally found in specialized condensates called nucleolar fiber centers (FCs). It is well known that FC contributes to the synthesis of ribosomal RNA, a crucial component of the ribosome, the cellular machine that creates all of the proteins found in cells.

However, despite its importance in ribosome assembly, fibrous tissue appeared only about 300 million years ago; unicellular organisms, invertebrates, and early vertebrates (fish) do not have it.

According to the latest research, TCOF1 is necessary for the change from a "two-part" nucleolus to a "three-part" nucleolus. The scientists discovered that cells could only produce two nucleolar compartments in the absence of TCOF1. Also, when the researchers added TCOF1 to zebrafish embryos that normally have bipartite nucleoli, they were able to induce a third.

"TCOF1 not only produces the condensation, but it also rebuilds the nucleolus for us, showing that even the condensation reaction introduced into the nucleolus is sufficient to change the contents of the organelle," Calo says.

Scaffold evolution

The researchers also found that key areas of TCOF1 that help build scaffolds are less complex regions that are rich in glutamate. LCRs interact with other glutamate-rich domains of the adjacent TCOF1 molecule to help the protein assemble, which then attracts other proteins and biomolecules to help form the fibrillar center.

"This discovery is quite intriguing because it gives us a molecular control mechanism that allows us to identify it in animals that do not have a blood clot and delete it in animals that have. This can help us resolve the business relationship and determine what the third party's role is." Jaberi-Lashkari says.

Based on the results of this study, the researchers speculated that cell condensations that arose early in evolutionary history may begin to be powered by a protein because TCOF1 supports the fibrillar center, but gradually transforms into many pathways.

"Our hypothesis is supported by the data in the article that condensation may be due to the scaffolding materials involved and changing over time," Calo says.

Diseases such as Amyotrophic lateral sclerosis (ALS), Huntington's chorea, and cancer have all been linked to the making of particular kinds of membrane-less organelles. "Our research asks why these assemblies are developing in each of these circumstances and what the scaffold is inside these assemblies. And if we can comprehend that better, I believe we will be able to treat these diseases more effectively." Lee says.