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The Dark Matter of the Human Proteome

dna repair proteins microproteins smorf proteome

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#1 Engadin

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Posted 03 April 2019 - 08:03 PM


Advances in the functional characterization of newly discovered microproteins hint at diverse roles in health and disease.

 

In 2014, as I started my doctoral work at the lab of Alan Saghatelian at the Salk Institute for Biological Studies in La Jolla, California, the idea that there were tiny proteins in our cells that had long been overlooked by researchers was gaining traction. Researchers had recently recognized that the genome contained genes that were so small that they had been missed by traditional genome annotation methods, and targeted searching for protein-coding snippets of DNA had suggested there may be many thousands of so-called micro­proteins hard at work in our cells.

 

Before I joined the lab, Saghatelian’s group had developed a new approach to validate the existence of some 400 microproteins across multiple human cell lines and tissues. Other labs were similarly confirming the existence of these predicted peptides, pointing to the ubiquitous nature of microproteins. But what were they doing?.

 

The functions of the microproteins in biological context quickly became a focus of the field. Some researchers, including Saghatelian’s group, approached this research question by looking for proteins that interacted with the micro­protein of interest. In the same year that I started in the lab, the group published its work on the microprotein MRI-2, later renamed CYREN, which appears to regulate DNA repair. It was one of only a handful of microproteins that had been characterized, yet many studies estimated that there were hundreds or thousands more to be looked at. The scope of the field was massive. I knew I wanted in on this burgeoning area of research.

 

Microproteins are not the cell’s only tiny proteins, but similarly diminutive peptide hormones, such as insulin, only become biologically active after they’re cleaved from larger precursor proteins. Microproteins, on the other hand, start out that way. They are translated from a small open reading frame (smORF) directly into their active form. These smORFs are so tiny, in fact, that researchers overlooked them in the early 2000s as they began predicting all the protein-coding regions in the newly sequenced human genome; they used a minimum length cutoff of 100 codons for gene assignment to decrease the rate of false positives. But over the past 10 years, developments in genomics and proteomics methods have revealed hundreds to thousands of smORFs.

 

Nailing down the functions of the microproteins they encode has been challenging. For one, newly discovered protein-coding smORFs often fail to produce detectable amounts of protein when cloned and expressed in cultured human cells, likely because their size makes the tiny proteins unstable. Moreover, most of these novel microproteins aren’t homologous to any known protein in any organism, making it extremely difficult to develop and test hypotheses about their functions.

 

Despite the challenges, researchers are making progress in characterizing the functions of the putative microproteins that have already been found in the genetic code. New techniques for identify­ing protein-microprotein interactions reveal how the tiny molecules function in the context of larger protein complexes, and where those complexes tend to be found in the cell. In the last five years, our group and others have uncovered plausible roles for microproteins in development, metabolism, muscle function, DNA repair, and mitochondrial activity, and some may even have links to disease. We are only beginning to scratch the surface of this field. Hundreds more microproteins have been detected across human cell lines and tissues, and thousands are predicted to exist across species on the basis of genomic data.

 

Uncopyable and very didactic schemes ahead. So please go ahead in the article at the source: https://www.the-scie...-proteome-65628







Also tagged with one or more of these keywords: dna repair, proteins, microproteins, smorf, proteome

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