Genome complexity: microprotein controls (Introduction)

by David Turell , Monday, April 01, 2019, 23:13 (1852 days ago) @ David Turell

Most active biochemical molecules are huge, but there are tiny ones that are functional:

https://www.the-scientist.com/features/the-dark-matter-of-the-human-proteome-65628?utm_...

"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.

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"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.

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"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.

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"These techniques have identified evidence of smORFs in diverse types of supposedly noncoding RNA, including introns of pre-mRNAs, long noncoding RNAs, and primary transcripts of micro­RNAs and ribosomal RNAs. The next step is to identify the microproteins they encode and understand their biological importance.

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"Over the past couple of years, these approaches have revealed that, unlike peptide hormones, which carry signals from one cell to another, microproteins function within the cell by interacting with larger protein complexes.

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"These findings emphasize the importance of further investigations to discover and characterize novel smORFs and the microproteins they encode. Biochemical studies show that microproteins use short sequences of just two to four amino acids to interact with larger protein complexes to regulate biology. "

Comment: I've always suspected there were many hidden layers of genome activity. More will be found. We can't exist as humans with just 20,000 genes described. This is an important beginning to find more of the guidance of multiple dynamic processes.