Discovery and characterization of smORF-encoded bioactive polypeptides

Saghatelian, Alan; Couso, Juan Pablo

doi:10.1038/nchembio.1964

Cited by 238 publications

(251 citation statements)

References 83 publications

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“…[3][4][5] Moreover, peptide products can be detected with increased sensitivity by improved mass-spectrometry. [6][7][8][9][10][11][12] Based on these studies it is becoming increasingly clear that many regions outside of annotated protein-coding ORFs are translated. New translated regions have not only been identified in transcripts thought to be non-coding, but also upstream of a large fraction of protein-coding ORFs (so-called upstream ORFs, uORFs).…”

Section: Introductionmentioning

confidence: 99%

Decoding sORF translation – from small proteins to gene regulation

2016

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Translation is best known as the fundamental mechanism by which the ribosome converts a sequence of nucleotides into a string of amino acids. Extensive research over many years has elucidated the key principles of translation, and the majority of translated regions were thought to be known. The recent discovery of wide-spread translation outside of annotated protein-coding open reading frames (ORFs) came therefore as a surprise, raising the intriguing possibility that these newly discovered translated regions might have unrecognized protein-coding or gene-regulatory functions. Here, we highlight recent findings that provide evidence that some of these newly discovered translated short ORFs (sORFs) encode functional, previously missed small proteins, while others have regulatory roles. Based on known examples we will also speculate about putative additional roles and the potentially much wider impact that these translated regions might have on cellular homeostasis and gene regulation.

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Section: Introductionmentioning

confidence: 99%

Decoding sORF translation – from small proteins to gene regulation

2016

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“…There is a growing body of evidence that lncRNA can produce short peptides from small open reading frames (smORFs) to regulate biological processes (51). The status of both lncRNA, and indeed, smORFs remains to be investigated in SCST.…”

Section: The 'Mirna-ome' and Other Non-coding Rnasmentioning

confidence: 99%

Genetics and genomics of ovarian sex cord‐stromal tumors

2017

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Ovarian sex cord‐stromal tumors (SCST) represent approximately 8% of malignant ovarian tumors. The most common are granulosa cell tumors (GCT) which account for approximately 90% of malignant SCST. Recent studies have unraveled the key genomic and genetic events contributing to their pathogenesis. SCST are found in the hereditary syndromes: Peutz‐Jeghers syndrome, Ollier disease and Maffucci syndrome, and DICER1 syndrome. Genomic studies have largely been limited to GCT where a number of recurring chromosomal abnormalities (monsomy and trisomy) have been identified although their contribution to pathogenesis remains unclear. In addition to the recurrent DICER1 mutations reported in non‐hereditary cases of Sertoli cell and Sertoli–Leydig cell tumors, recurrent somatic mutations in both the juvenile (j) and adult (a) forms of GCT have been reported. Approximately 30% of jGCT contain a somatic mutation, the gsp oncogene, while a further 60% have an activating mutation in the AKT gene. In the case of aGCT, a well characterized mutation in the FOXL2 transcription factor (FOXL2 C134W) is found in almost all cases, which arguably defines the disease, although the molecular events that determine the stage, behavior and prognosis of aGCT remain to be determined.

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“…A number of GBPs are small proteins, less than 150 amino acids, and over the past decades the functions of many small proteins have been discovered to be critical to various cellular processes, primarily through serendipitous studies (16). For example, galectin-1 with an affinity for β-galactose (Gal) was shown to be essential to neuronal cell differentiation and be associated with malignant tumor progression in human (17,18).…”

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confidence: 99%

“…For example, galectin-1 with an affinity for β-galactose (Gal) was shown to be essential to neuronal cell differentiation and be associated with malignant tumor progression in human (17,18). Small proteins also regulate essential cellular processes of bacteria (e.g., the 43-aa SgrS) (19), yeast (20), and animals (16). In recent years, systems biology studies have demonstrated that organisms commonly express hundreds of small proteins that often have no characterized homologs (16,(21)(22)(23).…”

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confidence: 99%

“…Small proteins also regulate essential cellular processes of bacteria (e.g., the 43-aa SgrS) (19), yeast (20), and animals (16). In recent years, systems biology studies have demonstrated that organisms commonly express hundreds of small proteins that often have no characterized homologs (16,(21)(22)(23). Accurately assigning a biochemical, cellular, or physiological function to these proteins is a rapidly evolving research area whose advances require the integration of multiple disciplines (16,24).…”

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confidence: 99%

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Cytotoxic protein from the mushroom Coprinus comatus possesses a unique mode for glycan binding and specificity

Zhang

Yang

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Glycans possess significant chemical diversity; glycan binding proteins (GBPs) recognize specific glycans to translate their structures to functions in various physiological and pathological processes. Therefore, the discovery and characterization of novel GBPs and characterization of glycan-GBP interactions are significant to provide potential targets for therapeutic intervention of many diseases. Here, we report the biochemical, functional, and structural characterization of a 130-amino-acid protein, Y3, from the mushroom Coprinus comatus. Biochemical studies of recombinant Y3 from a yeast expression system demonstrated the protein is a unique GBP. Additionally, we show that Y3 exhibits selective and potent cytotoxicity toward human T-cell leukemia Jurkat cells compared with a panel of cancer cell lines via inducing caspase-dependent apoptosis. Screening of a glycan array demonstrated GalNAcβ1-4(Fucα1-3)GlcNAc (LDNF) as a specific Y3-binding ligand. To provide a structural basis for function, the crystal structure was solved to a resolution of 1.2 Å, revealing a single-domain αβα-sandwich motif. Two monomers were dimerized to form a large 10-stranded, antiparallel β-sheet flanked by α-helices on each side, representing a unique oligomerization mode among GBPs. A large glycan binding pocket extends into the dimeric interface, and docking of LDNF identified key residues for glycan interactions. Disruption of residues predicted to be involved in LDNF/Y3 interactions resulted in the significant loss of binding to Jurkat T-cells and severely impaired their cytotoxicity. Collectively, these results demonstrate Y3 to be a GBP with selective cytotoxicity toward human T-cell leukemia cells and indicate its potential use in cancer diagnosis and treatment.

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Discovery and characterization of smORF-encoded bioactive polypeptides

Cited by 238 publications

References 83 publications

Decoding sORF translation – from small proteins to gene regulation

Decoding sORF translation – from small proteins to gene regulation

Genetics and genomics of ovarian sex cord‐stromal tumors

Cytotoxic protein from the mushroom Coprinus comatus possesses a unique mode for glycan binding and specificity

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