De novo birth of functional microproteins in the human lineage

Vakirlis, Nikolaos; Vance, Zoe; Duggan, Kate M.; McLysaght, Aoife

doi:10.1016/j.celrep.2022.111808

Cited by 56 publications

(54 citation statements)

References 82 publications

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“…We further estimated that 4,101 sORFs emerged de novo during primatomorpha evolution, including 162 human-specific ones. When translated into stable microproteins, this would increase the number of human-specific de novo microproteins reported previously 7 by an order of magnitude. This substantiates observations that sporadic protein evolution “from scratch” may occur at a higher rate than previously thought.…”

Section: Discussionmentioning

confidence: 97%

“…Microproteins have gained increasing attention in recent years, but the biological significance of human evolutionarily young and very small microproteins has remained less well studied. 2 , 5 , 7 , 22 , 60 , 61 , 62 , 63 We aimed to address this knowledge gap by investigating the evolutionary origins and interactomes of the putative microproteins and peptides encoded by young and very small ORFs.…”

Section: Discussionmentioning

confidence: 99%

“… 3 Many human microproteins have been selected for functional characterization based on high inter-species conservation 2 , 4 and a minimum amino acid (aa) size. However, evolutionarily young microproteins can have biological roles and have for instance been implicated in cell survival, 5 , 6 , 7 human brain development, 8 and cancer. 9 , 10 , 11 Similarly, a lower size cutoff for protein investigations seems unjustified: peptides as small as 11 aa can control morphogenetic development in insects 12 , 13 , 14 and muscle metabolism in humans, 15 respectively, and short bioactive peptides cleaved from bigger precursor proteins can function as peptide hormones.…”

Section: Introductionmentioning

confidence: 99%

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Evolutionary origins and interactomes of human, young microproteins and small peptides translated from short open reading frames

et al. 2023

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Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Evolutionary origins and interactomes of human, young microproteins and small peptides translated from short open reading frames

et al. 2023

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“…Despite the fact that research on orphan proteins is a hot topic, largely due to its evolutionary implications 64 , we were able to find only three crystal structures of orphan proteins in the PDB. Fig.…”

Section: Resultsmentioning

confidence: 90%

“…All the proteins in Group 3 expressed in soluble form, and had low secondary structure. We used all three structure prediction tools to model the structures of several members of Group Despite the fact that research on orphan proteins is a hot topic, largely due to its evolutionary implications 64 , we were able to find only three crystal structures of orphan proteins in the PDB.…”

Section: Resultsmentioning

confidence: 99%

Do Newly Born Orphan Proteins Resemble Never Born Proteins? A Study Using Three Deep Learning Algorithms

Liu

Yuan

Shao

et al. 2022

Preprint

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Newly Born proteins, devoid of detectable homology to any other proteins, known as orphan proteins, occur in a single species or within a taxonomically restricted gene family. They are generated by expression of novel Open Reading Frames, and appear throughout evolution. We used the recently developed programs for predicting protein structures, RoseTTAFold and AlphaFold2, to compare such Newly Born proteins to random polypeptides generated by shuffling sequences of native proteins, which have been called ‘Never Born’ proteins. The two programs were used to compare the structures of two sets of four Never Born proteins, one set that had been expressed and shown to be intrinsically disordered, and a second set that had been shown experimentally to possess substantial secondary structure. Since the programs rely to a large extent on multisequence alignment, the models generated were scored as being of low quality. However, a significant pattern emerged when the models generated by RoseTTAFold were examined. Specifically, all four members of Group 1 were shown to be very extended, as would be expected for intrinsically disordered proteins. In contrast, all four members of Group 2 appeared to be compact, and possessed substantial secondary structure. As a further control, both programs predicted unfolded structures for three well characterized intrinsically disordered proteins. The two programs were used to predict the structures of two orphan proteins whose crystal structures have been solved, both of which display novel folds. RoseTTAFold predicted both structures very well, whereas AlphaFold2 predicted only one well. The two programs were used to predict the structures of five orphan proteins with well-identified biological functions, one of which is predicted to be intrinsically disordered, and four to be folded. Both programs displayed the intrinsically disordered protein as an unfolded structure. RoseTTAFold displayed all four of those predicted to be folded as compact folded structures, with apparent novel folds, as determined by Dali and Foldseek. It is plausible that new biological functions may be implemented by orphan proteins due to their novel folds.

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Microproteins—Discovery, structure, and function

Mohsen,

Martel,

Slavoff

2023

Proteomics

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Advances in proteogenomic technologies have revealed hundreds to thousands of translated small open reading frames (sORFs) that encode microproteins in genomes across evolutionary space. While many microproteins have now been shown to play critical roles in biology and human disease, a majority of recently identified microproteins have little or no experimental evidence regarding their functionality. Computational tools have some limitations for analysis of short, poorly conserved microprotein sequences, so additional approaches are needed to determine the role of each member of this recently discovered polypeptide class. A currently underexplored avenue in the study of microproteins is structure prediction and determination, which delivers a depth of functional information. In this review, we provide a brief overview of microprotein discovery methods, then examine examples of microprotein structures (and, conversely, intrinsic disorder) that have been experimentally determined using crystallography, cryo‐electron microscopy, and NMR, which provide insight into their molecular functions and mechanisms. Additionally, we discuss examples of predicted microprotein structures that have provided insight or context regarding their function. Analysis of microprotein structure at the angstrom level, and confirmation of predicted structures, therefore, has potential to identify translated microproteins that are of biological importance and to provide molecular mechanism for their in vivo roles.

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De novo birth of functional microproteins in the human lineage

Cited by 56 publications

References 82 publications

Evolutionary origins and interactomes of human, young microproteins and small peptides translated from short open reading frames

Evolutionary origins and interactomes of human, young microproteins and small peptides translated from short open reading frames

Do Newly Born Orphan Proteins Resemble Never Born Proteins? A Study Using Three Deep Learning Algorithms

Microproteins—Discovery, structure, and function

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