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Modifications of Protein Termini 2.0
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Modifications of Protein Termini 2.0

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: closed (15 March 2023) | Viewed by 11553

Special Issue Editor

Dr. Thierry Meinnel

E-Mail Website
Guest Editor
Institute for Integrative Biology of the Cell, Universite Paris-Saclay, 91198 Gif-sur-Yvette CEDEX, France
Interests: N-terminus; N-terminomics; proteostasis; protein modifications; fatty acylation; protein acetylation; myristoylation; deformylation; proteomics; methionine excision; enzyme activity inhibition; plant biology; bacteriology
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Protein-borne information not only relies on genetic code and its translation into amino acids but also on additional marks—so-called protein modifications—which are progressively added onto the elongating or fully-folded polypeptide chain. More than 400 modifications have been described to date, each adding new features that are required in the course of life and fate of the protein. Some protein modifications accompany the protein across its entire physiological role while others only temporarily tag the protein leading, in extreme cases, to immediate programmed death. Though protein modification can theoretically occur anywhere, exposed loops are strongly favored sites due to both their higher accessibility and reactivity. Among them, protein N- and C-termini are the only conserved sites that promote extended modification temporality together with a remarkable diversity of chemical reactions and modifications. Dedicated enzymes catalyze most such modifications while some reactions only rely on physiological conditions. The past ten years in the field have shown how rich the modification panel is and that protein termini modifications occur in all living organisms.

This Special Issue will publish original research articles and reviews, including perspectives in the field on the current understanding of modifications of protein termini. Manuscripts on molecular mechanisms and new quantitative approaches for measuring the modification levels and yields are welcome.

Dr. Thierry Meinnel
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • N-terminal modifications
  • C-terminal modification
  • proteolysis
  • protein acyl- and acetyl-ation
  • oxidation
  • N-end rule
  • membrane targeting signals
  • proteoforms

Published Papers (6 papers)

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Research

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16 pages, 20116 KiB  
Article
No Substrate Left behind—Mining of Shotgun Proteomics Datasets Rescues Evidence of Proteolysis by SARS-CoV-2 3CLpro Main Protease
by Peter A. Bell and Christopher M. Overall
Int. J. Mol. Sci. 2023, 24(10), 8723; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24108723 - 13 May 2023
Cited by 2 | Viewed by 1507
Abstract
Proteolytic processing is the most ubiquitous post-translational modification and regulator of protein function. To identify protease substrates, and hence the function of proteases, terminomics workflows have been developed to enrich and detect proteolytically generated protein termini from mass spectrometry data. The mining of [...] Read more.
Proteolytic processing is the most ubiquitous post-translational modification and regulator of protein function. To identify protease substrates, and hence the function of proteases, terminomics workflows have been developed to enrich and detect proteolytically generated protein termini from mass spectrometry data. The mining of shotgun proteomics datasets for such ‘neo’-termini, to increase the understanding of proteolytic processing, is an underutilized opportunity. However, to date, this approach has been hindered by the lack of software with sufficient speed to make searching for the relatively low numbers of protease-generated semi-tryptic peptides present in non-enriched samples viable. We reanalyzed published shotgun proteomics datasets for evidence of proteolytic processing in COVID-19 using the recently upgraded MSFragger/FragPipe software, which searches data with a speed that is an order of magnitude greater than many equivalent tools. The number of protein termini identified was higher than expected and constituted around half the number of termini detected by two different N-terminomics methods. We identified neo-N- and C-termini generated during SARS-CoV-2 infection that were indicative of proteolysis and were mediated by both viral and host proteases—a number of which had been recently validated by in vitro assays. Thus, re-analyzing existing shotgun proteomics data is a valuable adjunct for terminomics research that can be readily tapped (for example, in the next pandemic where data would be scarce) to increase the understanding of protease function and virus–host interactions, or other diverse biological processes. Full article
(This article belongs to the Special Issue Modifications of Protein Termini 2.0)
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14 pages, 2943 KiB  
Article
Orthodontic Compression Enhances Macrophage M2 Polarization via Histone H3 Hyperacetylation
by Yao Wang, Sabine Groeger, Jiawen Yong and Sabine Ruf
Int. J. Mol. Sci. 2023, 24(4), 3117; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24043117 - 04 Feb 2023
Cited by 3 | Viewed by 2021
Abstract
Orthodontic tooth movement is a complex periodontal remodeling process triggered by compression that involves sterile inflammation and immune responses. Macrophages are mechanically sensitive immune cells, but their role in orthodontic tooth movement is unclear. Here, we hypothesize that orthodontic force can activate macrophages, [...] Read more.
Orthodontic tooth movement is a complex periodontal remodeling process triggered by compression that involves sterile inflammation and immune responses. Macrophages are mechanically sensitive immune cells, but their role in orthodontic tooth movement is unclear. Here, we hypothesize that orthodontic force can activate macrophages, and their activation may be associated with orthodontic root resorption. After force-loading and/or adiponectin application, the migration function of macrophages was tested via scratch assay, and Nos2, Il1b, Arg1, Il10, ApoE, and Saa3 expression levels were detected using qRT-PCR. Furthermore, H3 histone acetylation was measured using an acetylation detection kit. The specific inhibitor of H3 histone, I-BET762, was deployed to observe its effect on macrophages. In addition, cementoblasts were treated with macrophage-conditioned medium or compression force, and OPG production and cellular migration were measured. We further detected Piezo1 expression in cementoblasts via qRT-PCR and Western-blot, and its effect on the force-induced impairment of cementoblastic functions was also analyzed. Compressive force significantly inhibited macrophage migration. Nos2 was up-regulated 6 h after force-loading. Il1b, Arg1, Il10, Saa3, and ApoE increased after 24 h. Meanwhile, higher H3 histone acetylation was detected in the macrophages subjected to compression, and I-BET762 dampened the expression of M2 polarization markers (Arg1 and Il10). Lastly, even though the activated macrophage-conditioned medium showed no effect on cementoblasts, compressive force directly impaired cementoblastic function by enhancing mechanoreceptor Piezo1. Compressive force activates macrophages; specifically, it causes M2 polarization via H3 histone acetylation in the late stage. Compression-induced orthodontic root resorption is macrophage-independent, but it involves the activation of mechanoreceptor Piezo1. Full article
(This article belongs to the Special Issue Modifications of Protein Termini 2.0)
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19 pages, 4209 KiB  
Article
Enzymatic Construction of DARPin-Based Targeted Delivery Systems Using Protein Farnesyltransferase and a Capture and Release Strategy
by Yi Zhang, Yiao Wang, Safak Uslu, Sneha Venkatachalapathy, Mohammad Rashidian, Jonas V. Schaefer, Andreas Plückthun and Mark D. Distefano
Int. J. Mol. Sci. 2022, 23(19), 11537; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms231911537 - 29 Sep 2022
Cited by 1 | Viewed by 2016
Abstract
Protein-based conjugates have been extensively utilized in various biotechnological and therapeutic applications. In order to prepare homogeneous conjugates, site-specific modification methods and efficient purification strategies are both critical factors to be considered. The development of general and facile conjugation and purification strategies is [...] Read more.
Protein-based conjugates have been extensively utilized in various biotechnological and therapeutic applications. In order to prepare homogeneous conjugates, site-specific modification methods and efficient purification strategies are both critical factors to be considered. The development of general and facile conjugation and purification strategies is therefore highly desirable. Here, we apply a capture and release strategy to create protein conjugates based on Designed Ankyrin Repeat Proteins (DARPins), which are engineered antigen-binding proteins with prominent affinity and selectivity. In this case, DARPins that target the epithelial cell adhesion molecule (EpCAM), a diagnostic cell surface marker for many types of cancer, were employed. The DARPins were first genetically modified with a C-terminal CVIA sequence to install an enzyme recognition site and then labeled with an aldehyde functional group employing protein farnesyltransferase. Using a capture and release strategy, conjugation of the labeled DARPins to a TAMRA fluorophore was achieved with either purified proteins or directly from crude E. coli lysate and used in subsequent flow cytometry and confocal imaging analysis. DARPin-MMAE conjugates were also prepared yielding a construct manifesting an IC50 of 1.3 nM for cell killing of EpCAM positive MCF-7 cells. The method described here is broadly applicable to enable the streamlined one-step preparation of protein-based conjugates. Full article
(This article belongs to the Special Issue Modifications of Protein Termini 2.0)
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28 pages, 14618 KiB  
Article
Extended N-Terminal Acetyltransferase Naa50 in Filamentous Fungi Adds to Naa50 Diversity
by Jonas Weidenhausen, Jürgen Kopp, Carmen Ruger-Herreros, Frank Stein, Per Haberkant, Karine Lapouge and Irmgard Sinning
Int. J. Mol. Sci. 2022, 23(18), 10805; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms231810805 - 16 Sep 2022
Cited by 2 | Viewed by 1946
Abstract
Most eukaryotic proteins are N-terminally acetylated by a set of Nα acetyltransferases (NATs). This ancient and ubiquitous modification plays a fundamental role in protein homeostasis, while mutations are linked to human diseases and phenotypic defects. In particular, Naa50 features species-specific differences, as it [...] Read more.
Most eukaryotic proteins are N-terminally acetylated by a set of Nα acetyltransferases (NATs). This ancient and ubiquitous modification plays a fundamental role in protein homeostasis, while mutations are linked to human diseases and phenotypic defects. In particular, Naa50 features species-specific differences, as it is inactive in yeast but active in higher eukaryotes. Together with NatA, it engages in NatE complex formation for cotranslational acetylation. Here, we report Naa50 homologs from the filamentous fungi Chaetomium thermophilum and Neurospora crassa with significant N- and C-terminal extensions to the conserved GNAT domain. Structural and biochemical analyses show that CtNaa50 shares the GNAT structure and substrate specificity with other homologs. However, in contrast to previously analyzed Naa50 proteins, it does not form NatE. The elongated N-terminus increases Naa50 thermostability and binds to dynein light chain protein 1, while our data suggest that conserved positive patches in the C-terminus allow for ribosome binding independent of NatA. Our study provides new insights into the many facets of Naa50 and highlights the diversification of NATs during evolution. Full article
(This article belongs to the Special Issue Modifications of Protein Termini 2.0)
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15 pages, 12348 KiB  
Article
Functional Interplay between Arginyl-tRNA Synthetases and Arginyltransferase
by Irem Avcilar-Kucukgoze, Brittany MacTaggart and Anna Kashina
Int. J. Mol. Sci. 2022, 23(17), 10160; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms231710160 - 05 Sep 2022
Viewed by 1117
Abstract
Protein arginylation, mediated by arginyltransferase ATE1, is a post-translational modification of emerging biological importance that consists of transfer of the amino acid Arg to protein and peptide substrates. ATE1 utilizes charged tRNAArg as the donor of the arginyl group, which depends on [...] Read more.
Protein arginylation, mediated by arginyltransferase ATE1, is a post-translational modification of emerging biological importance that consists of transfer of the amino acid Arg to protein and peptide substrates. ATE1 utilizes charged tRNAArg as the donor of the arginyl group, which depends on the activity of Arg-tRNA synthetases (RARS) and is also utilized in translation. The mechanisms that regulate the functional balance among ATE1, RARS and translation are unknown. Here, we addressed the question of how these two enzymes can partition Arg-tRNAArg to functionally distinct pathways using an intracellular arginylation sensor in cell lines with overexpression or deletion of ATE1 and RARS isoforms. We found that arginylation levels depend on the physiological state of the cells but are not directly affected by translation activity or the availability of RARS isoforms. However, displacement of RARS from the multi-synthetase complex leads to an increase in intracellular arginylation independently of RARS enzymatic activity. This effect is accompanied by ATE1′s redistribution into the cytosol. Our results provide the first comprehensive analysis of the interdependence among translation, arginyl-tRNA synthesis and arginylation. Full article
(This article belongs to the Special Issue Modifications of Protein Termini 2.0)
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Review

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22 pages, 3267 KiB  
Review
From Nucleus to Membrane: A Subcellular Map of the N-Acetylation Machinery in Plants
by Marlena Pożoga, Laura Armbruster and Markus Wirtz
Int. J. Mol. Sci. 2022, 23(22), 14492; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232214492 - 21 Nov 2022
Cited by 3 | Viewed by 2259
Abstract
N-terminal acetylation (NTA) is an ancient protein modification conserved throughout all domains of life. N-terminally acetylated proteins are present in the cytosol, the nucleus, the plastids, mitochondria and the plasma membrane of plants. The frequency of NTA differs greatly between these subcellular compartments. [...] Read more.
N-terminal acetylation (NTA) is an ancient protein modification conserved throughout all domains of life. N-terminally acetylated proteins are present in the cytosol, the nucleus, the plastids, mitochondria and the plasma membrane of plants. The frequency of NTA differs greatly between these subcellular compartments. While up to 80% of cytosolic and 20–30% of plastidic proteins are subject to NTA, NTA of mitochondrial proteins is rare. NTA alters key characteristics of proteins such as their three-dimensional structure, binding properties and lifetime. Since the majority of proteins is acetylated by five ribosome-bound N-terminal acetyltransferases (Nats) in yeast and humans, NTA was long perceived as an exclusively co-translational process in eukaryotes. The recent characterization of post-translationally acting plant Nats, which localize to the plasma membrane and the plastids, has challenged this view. Moreover, findings in humans, yeast, green algae and higher plants uncover differences in the cytosolic Nat machinery of photosynthetic and non-photosynthetic eukaryotes. These distinctive features of the plant Nat machinery might constitute adaptations to the sessile lifestyle of plants. This review sheds light on the unique role of plant N-acetyltransferases in development and stress responses as well as their evolution-driven adaptation to function in different cellular compartments. Full article
(This article belongs to the Special Issue Modifications of Protein Termini 2.0)
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