MIT Biologists Glean New Insight Into Repetitive Protein Sequences

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MIT researchers used a technique called dot-plot matrix, which is a way to visually represent amino acid sequences, to compare protein sequences known as “low-complexity regions” across many different species. Credit: Courtesy of the researchers, and edited by MIT News.

Computational analysis reveals that many repetitive sequences are shared across proteins and are similar in species from bacteria to humans.

Approximately 70 percent of all human proteins include at least one sequence consisting of a single amino[{” attribute=””>acid repeated many times, with a few other

Amino acids are a set of organic compounds used to build proteins. There are about 500 naturally occurring known amino acids, though only 20 appear in the genetic code. Proteins consist of one or more chains of amino acids called polypeptides. The sequence of the amino acid chain causes the polypeptide to fold into a shape that is biologically active. The amino acid sequences of proteins are encoded in the genes. Nine proteinogenic amino acids are called “essential” for humans because they cannot be produced from other compounds by the human body and so must be taken in as food.

” data-gt-translate-attributes=”[{” attribute=””>amino acids sprinkled in. These “low-complexity regions” (LCRs) are also found in the proteins of most other organisms.

Although the proteins that contain these sequences have many different functions,

Differences between LCRs of different species were also found by the research team. They showed that these species-specific LCR sequences correspond to species-specific functions, such as forming plant cell walls.

Lee and graduate student Nima Jaberi-Lashkari are the lead authors of the study, which was recently published in the journal eLife. Eliezer Calo, an assistant professor of biology at MIT, is the senior author of the paper.

Repetitive Sequences Are Shared Across Proteins

Using computational analysis, researchers have found that many repetitive sequences are shared across proteins and are similar in species from bacteria to humans. Credit: Courtesy of the researchers

Large-scale study

Previous research revealed that LCRs are involved in a variety of cellular processes, including cell adhesion and

Finding these sequences and then studying their functions individually is a time-consuming process, so the scientists decided to use bioinformatics — an approach that uses computational methods to analyze large sets of biological data — to evaluate them as a larger group.

Bioinformatics is a relatively new scientific subdiscipline that incorporates elements of biology and computer science together for the purpose of developing efficient and robust methods for the analyses and interpretation of large amounts of biological data, such as DNA,

As one demonstration, the team of researchers picked out a human protein, known as RPA43, which has three lysine-rich LCRs. This protein is one of many subunits that make up an enzyme called RNA polymerase 1, which synthesizes ribosomal RNA. The scientists discovered that the copy number of lysine-rich LCRs is important for helping the protein integrate into the nucleolus, the organelle responsible for synthesizing ribosomes.

Biological assemblies

In a comparison of the proteins found in eight different species, the researchers found that some LCR types are highly conserved between species, meaning that the sequences have changed very little over evolutionary timescales. These sequences tend to be found in proteins and cell structures that are also highly conserved, such as the nucleolus.

“These sequences seem to be important for the assembly of certain parts of the nucleolus,” Lee says. “Some of the principles that are known to be important for higher order assembly seem to be at play because the copy number, which might control how many interactions a protein can make, is important for the protein to integrate into that compartment.”

The MIT team also found differences between LCRs seen in two different types of proteins that are involved in nucleolus assembly. They discovered that a nucleolar protein known as TCOF contains many glutamine-rich LCRs that can help scaffold the formation of assemblies, while nucleolar proteins with only a few of these glutamic acid-rich LCRs could be recruited as clients (proteins that interact with the scaffold).

Another structure that appears to have many conserved LCRs is the nuclear speckle, which is found inside the cell nucleus. The researchers also found many similarities between LCRs that are involved in forming larger-scale assemblies such as the extracellular matrix, a network of molecules that provides structural support to cells in plants and animals.

The research team also found examples of structures with LCRs that seem to have diverged between species. For example, plants have distinctive LCR sequences in the proteins that they use to scaffold their cell walls, and these LCRs are not seen in other types of organisms.

Now the researchers plan to expand their LCR analysis to additional species.

“There’s so much to explore, because we can expand this map to essentially any species,” Lee says. “That gives us the opportunity and the framework to identify new biological assemblies.”

Reference: “A unified view of low complexity regions (LCRs) across species” by Byron Lee, Nima Jaberi-Lashkari and Eliezer Calo, 13 September 2022, eLife.
DOI: 10.7554/eLife.77058

The research was funded by the National Institute of General Medical Sciences, National Cancer Institute, the Ludwig Center at MIT, a National Institutes of Health Pre-Doctoral Training Grant, and the Pew Charitable Trusts.

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