Although human genes are often subject to alternative splicing—a post-transcriptional mechanism that allows a single gene to code for multiple proteins—the resulting protein ensembles are seldom evaluated systematically. A set of exceptions, however, has been compiled. It consists of the aminoacyl tRNA synthetases (AARSs) and their variants. The variants are derivative species—fragments, really—that lack the catalytic activity of full AARSs but still appear to serve biological functions.

AARSs comprise a group of 20 enzymes whose most basic function is to connect the nucleotide codes contained in genes to their corresponding protein building blocks. These enzymes, which are of ancient lineage, are found in all life forms. And now, according to new research, AARSs appear to have progressively accreted noncatalytic domains as the Tree of Life spread its boughs and branches. In one branch of the Tree of Life—humans—AARS variants appear to serve myriad functions that have little or nothing to do with protein translation. This surprising discovery highlights an intriguing oddity of protein evolution as well as a potentially valuable new class of therapeutic proteins and therapeutic targets.

Scientists have been finding evidence in recent years that AARS enzymes exist in greater complexity in more evolutionarily advanced organisms. To investigate further, a research team led by Paul Schimmel, Ph.D., a professor of molecular biology and chemistry at The Scripps Research Institute (TSRI), conducted a comprehensive search for alternative splice variants of AARSs to understand how splicing changes the domain organization and underlying architecture of each synthase.

Dr. Schimmel collaborated with colleagues at TSRI in California and Florida, the Hong Kong University of Science and Technology (HKUST), the San Diego biotech company aTyr Pharma (which Schimmel co-founded), and the Hong Kong biotech company Pangu Biopharma (an aTyr subsidiary). The collaborators identified 250 previously unknown gene-transcript variants of AARS in different human cell types. They also found that the new AARS variants often are produced only in specific cell types such as brain or immune cells and/or appear only during certain stages of development.

The results appear July 18 in the journal Science, in an article entitled, “Human tRNA synthetase catalytic nulls with diverse functions.” One variant selected for analysis turned out to be a powerful driver for the proliferation of muscle fiber cells in a laboratory dish. In addition, the study cited findings that specific AARSs appear to influence pathways associated with angiogenesis, inflammation, the immune response, mammalian target of rapamycin (mTOR) signaling, apoptosis, tumorigenesis, and interferon-g and p53 signaling.

“The work detailed here suggests that the universe of AARS-derived entities, which are active for nontranslational functions, may be far greater than anticipated,” wrote the authors. “The mechanism of erasing the canonical function, while adding noncatalytic domains, engenders a clear implementation of orthogonal functions.”

These findings further the work of aTyr Pharma, which dubs the AARS variants “Physiocrines.” The company is currently focused on Physiocrines that act as endogenous modulators of the immune and regenerative systems. Physiocrines, aTyr says, offer the opportunity for modulating biological pathways through newly discovered naturally occurring mechanisms, many of which may provide multiple therapeutic advantages, including improved efficacy and reduced side effect profiles compared to many existing therapeutics.

The research team of which aTyr was a part will now turn to more comprehensive studies of the new AARS variants and their specific functions. “These new protein variants represent a previously unrecognized layer of biology—the ramifications of this discovery are now unfolding,” said Dr. Schimmel. “We believe that these proteins have relevance to multiple human diseases. They represent a very important class of new protein therapeutics analogous to widely used injectable protein therapeutics such as growth hormone, insulin, erythropoietin, and granulocyte colony-stimulating factor.”

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