Microproteins: Overlooked regulators of physiology and disease

Hassel, Keira R.; Brito-Estrada, Omar; Makarewich, Catherine A.

doi:10.1016/j.isci.2023.106781

Cited by 21 publications

(10 citation statements)

References 149 publications

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“…It turned out that only four of these proteins were folded and one protein was partially folded, whereas the majority of proteins were in the molten globule state, were totally unfolded, or could not be produced. Various reviews summarize the specific challenges in the heterologous or homologous production of μ-proteins, in contrast to average-sized proteins ( Storz et al, 2014 ; Orr et al, 2020 ; Cassidy et al, 2021 ; Steinberg and Koch, 2021 ; Tharakan and Sawa, 2021 ; Chen et al, 2022 ; Gray et al, 2022 ; Leong et al, 2022 ; Schlesinger and Elsässer, 2022 ; Weidenbach et al, 2022 ; Zhang et al, 2022 ; Dong et al, 2023 ; Hassel et al, 2023 ).…”

Section: Discussionmentioning

confidence: 99%

“…Notable advancements encompass the establishment of ribosome profiling methods, advances in mass spectrometry (peptidomics), and enhancements in gene/ORF prediction through bioinformatics refinements. Several recent reviews summarize current knowledge about very small proteins in archaea, bacteria, and eukaryotes ( Storz et al, 2014 ; Orr et al, 2020 ; Cassidy et al, 2021 ; Steinberg and Koch, 2021 ; Tharakan and Sawa, 2021 ; Chen et al, 2022 ; Gray et al, 2022 ; Leong et al, 2022 ; Schlesinger and Elsässer, 2022 ; Weidenbach et al, 2022 ; Zhang et al, 2022 ; Dong et al, 2023 ; Hassel et al, 2023 ).…”

Section: Introductionmentioning

confidence: 99%

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Characterization of the zinc finger μ-protein HVO_0758 from Haloferax volcanii: biological roles, zinc binding, and NMR solution structure

Üresin,

Pyper,

Borst

et al. 2023

Front. Microbiol.

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It is increasingly recognized that very small proteins (μ-proteins) are ubiquitously found in all species of the three domains of life, and that they fulfill important functions. The halophilic archaeon Haloferax volcanii contains 282 μ-proteins of less than 70 amino acids. Notably, 43 of these contain two C(P)XCG motifs, suggesting their potential to complex a zinc ion. To explore the significance of these proteins, 16 genes encoding C(P)XCG proteins had been deleted, and the majority of mutants exhibited phenotypic differences to the wild-type. One such protein, HVO_2753, was thoroughly characterized in a previous study. In the present study an in-depth analysis of a second protein, HVO_0758, was performed. To achieve this goal, the HVO_0758 protein was produced heterologously in Escherichia coli and homologously in H. volcanii. The purified protein was characterized using various biochemical approaches and NMR spectroscopy. The findings demonstrated that HVO_0758 is indeed a bona fide zinc finger protein, and that all four cysteine residues are essential for folding. The NMR solution structure was solved, revealing that HVO_0758 is comprised of an N-terminal alpha helix containing several positively charged residues and a globular core with the zinc finger domain. The transcriptomes of the HVO_0758 deletion mutant and, for comparison, the HVO_2753 deletion mutant were analyzed with RNA-Seq and compared against that of the wild-type. In both mutants many motility and chemotaxis genes were down-regulated, in agreement to the phenotype of the deletion mutants, which had a swarming deficit. The two H. volcanii zinc-finger μ-proteins HVO_0758 and HVO_2753 showed many differences. Taken together, two zinc finger μ-proteins of H. volcanii have been characterized intensively, which emerged as pivotal contributors to swarming behavior and biofilm formation.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Characterization of the zinc finger μ-protein HVO_0758 from Haloferax volcanii: biological roles, zinc binding, and NMR solution structure

Üresin,

Pyper,

Borst

et al. 2023

Front. Microbiol.

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“…Thousands of microproteins (consisting of less than 100 amino acids) were recently described, however, their functional characterization is still incomplete due to their small size, which prohibits their tagging with fusion tags and to the fact that many of them are IDPs [ 118 , 119 ]. Moreover, their physiological function needs to be assessed in cellulo to uncover complex formation with other proteins.…”

Section: Fluorogenic Probes: General Considerationsmentioning

confidence: 99%

Bioorthogonal Reactions in Bioimaging

Kozma,

Kele

2024

Top Curr Chem (Z)

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Visualization of biomolecules in their native environment or imaging-aided understanding of more complex biomolecular processes are one of the focus areas of chemical biology research, which requires selective, often site-specific labeling of targets. This challenging task is effectively addressed by bioorthogonal chemistry tools in combination with advanced synthetic biology methods. Today, the smart combination of the elements of the bioorthogonal toolbox allows selective installation of multiple markers to selected targets, enabling multicolor or multimodal imaging of biomolecules. Furthermore, recent developments in bioorthogonally applicable probe design that meet the growing demands of superresolution microscopy enable more complex questions to be addressed. These novel, advanced probes enable highly sensitive, low-background, single- or multiphoton imaging of biological species and events in live organisms at resolutions comparable to the size of the biomolecule of interest. Herein, the latest developments in bioorthogonal fluorescent probe design and labeling schemes will be discussed in the context of in cellulo/in vivo (multicolor and/or superresolved) imaging schemes. The second part focuses on the importance of genetically engineered minimal bioorthogonal tags, with a particular interest in site-specific protein tagging applications to answer biological questions.

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“…Small open reading frames (smORFs) are unannotated ORFs encoding polypeptides less than 100 amino acids [ 1 ], which exist across prokaryotes and eukaryotes, from unicellular bacteria [ 2 ], yeast [ 3 ], to higher plants [ 4 ] and mammals [ 5 ]. smORF-encoded peptides (SEPs) are regarded as the major component in a hidden proteome we know very little about, which is far greater than the currently studied proteome [ 6 ].…”

Section: Introductionmentioning

confidence: 99%

sOCP: a framework predicting smORF coding potential based on TIS and in-frame features and effectively applied in the human genome

Peng,

Li,

Jiang

et al. 2024

Briefings in Bioinformatics

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Small open reading frames (smORFs) have been acknowledged to play various roles on essential biological pathways and affect human beings from diabetes to tumorigenesis. Predicting smORFs in silico is quite a prerequisite for processing the omics data. Here, we proposed the smORF-coding-potential-predicting framework, sOCP, which provides functions to construct a model for predicting novel smORFs in some species. The sOCP model constructed in human was based on in-frame features and the nucleotide bias around the start codon, and the small feature subset was proved to be competent enough and avoid overfitting problems for complicated models. It showed more advanced prediction metrics than previous methods and could correlate closely with experimental evidence in a heterogeneous dataset. The model was applied to Rattus norvegicus and exhibited satisfactory performance. We then scanned smORFs with ATG and non-ATG start codons from the human genome and generated a database containing about a million novel smORFs with coding potential. Around 72 000 smORFs are located on the lncRNA regions of the genome. The smORF-encoded peptides may be involved in biological pathways rare for canonical proteins, including glucocorticoid catabolic process and the prokaryotic defense system. Our work provides a model and database for human smORF investigation and a convenient tool for further smORF prediction in other species.

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Microproteins: Overlooked regulators of physiology and disease

Cited by 21 publications

References 149 publications

Characterization of the zinc finger μ-protein HVO_0758 from Haloferax volcanii: biological roles, zinc binding, and NMR solution structure

Characterization of the zinc finger μ-protein HVO_0758 from Haloferax volcanii: biological roles, zinc binding, and NMR solution structure

Bioorthogonal Reactions in Bioimaging

sOCP: a framework predicting smORF coding potential based on TIS and in-frame features and effectively applied in the human genome

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