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Life
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N-Terminal Protein Modifications and Human Diseases
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N-Terminal Protein Modifications and Human Diseases

A special issue of Life (ISSN 2075-1729). This special issue belongs to the section "Medical Research".

Deadline for manuscript submissions: closed (24 February 2023) | Viewed by 5909

Special Issue Editor

Dr. Yie Hwa Chang

E-Mail Website
Guest Editor
Edward A. Doisy Department of Biochemistry and Molecular Biology, Saint Louis University Medical School, Saint Louis, MO 63104, USA
Interests: angiogenesis; methionine aminopeptidases; protein processing; protein modifications; proteomics; cancer therapy; development of novel diagnostic technologies
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

N-terminal protein modifications include acetylation of the initiator methionine, removal of the initiator methionine followed by acetylation, myristoylation, or methylation of the newly exposed N-terminal residue. These modifications can change the chemical nature of a protein at its N-terminus, thereby affecting its stability, cellular localization, and/or biological function. Changes in N-terminal modifications play critical roles in human diseases and have been explored as potential targets for clinical intervention. For example, dysregulation of the enzymes responsible for N-methylation has been implicated in the pathogenesis of breast, colorectal, pancreatic, and lung cancer. Methionine aminopeptidase 2 (MetAP2) plays an essential role in angiogenesis and has been used as a target to develop drugs for the treatment of cancer, obesity, and diabetes. N-terminal acetyltransferase 4 (Nat4) has been associated with longevity. Mutations in the NAA10 gene, which encode N-alpha-acetyltransferase 10 (ARD1), have been associated with NAA10 syndrome and high-fat diet (HFD)-induced obesity. N-myristoylation plays a role in infectious diseases, parasitic diseases, and cancers. By synthesizing research on N-terminal protein modifications, further discoveries regarding the cellular pathways underlying human disease can be made, and new approaches to treat a variety of human diseases can be further explored.

This Special Issue will include research on the molecular mechanisms underlying the biological activities of the enzymes involved in N-terminal protein modifications, the crosstalk between these modification processes, new approaches for identifying and quantifying modifications, the links between modification processes with human disease outcomes, and innovative strategies for selectively interfering with these processes. We welcome the submission of original research (basic research or clinical research) and review manuscripts that meet the goals of this Special Issue.

Dr. Yie Hwa Chang
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. Life is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). 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 protein modifications
  • N-acetylation
  • N-myristoylation
  • N-methylation
  • Protein stability
  • Subcellular localization
  • angiogenesis

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Published Papers (2 papers)

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Research

17 pages, 3122 KiB  
Article
Phosphorylation Mimetic of Myosin Regulatory Light Chain Mitigates Cardiomyopathy-Induced Myofilament Impairment in Mouse Models of RCM and DCM
by Katarzyna Kazmierczak, Jingsheng Liang, Luis G. Maura, Natissa K. Scott and Danuta Szczesna-Cordary
Life 2023, 13(7), 1463; https://doi.org/10.3390/life13071463 - 28 Jun 2023
Cited by 2 | Viewed by 1772
Abstract
This study focuses on mimicking constitutive phosphorylation in the N-terminus of the myosin regulatory light chain (S15D-RLC) as a rescue strategy for mutation-induced cardiac dysfunction in transgenic (Tg) models of restrictive (RCM) and dilated (DCM) cardiomyopathy caused by mutations in essential (ELC, MYL3 [...] Read more.
This study focuses on mimicking constitutive phosphorylation in the N-terminus of the myosin regulatory light chain (S15D-RLC) as a rescue strategy for mutation-induced cardiac dysfunction in transgenic (Tg) models of restrictive (RCM) and dilated (DCM) cardiomyopathy caused by mutations in essential (ELC, MYL3 gene) or regulatory (RLC, MYL2 gene) light chains of myosin. Phosphomimetic S15D-RLC was reconstituted in left ventricular papillary muscle (LVPM) fibers from two mouse models of cardiomyopathy, RCM-E143K ELC and DCM-D94A RLC, along with their corresponding Tg-ELC and Tg-RLC wild-type (WT) mice. The beneficial effects of S15D-RLC in rescuing cardiac function were manifested by the S15D-RLC-induced destabilization of the super-relaxed (SRX) state that was observed in both models of cardiomyopathy. S15D-RLC promoted a shift from the SRX state to the disordered relaxed (DRX) state, increasing the number of heads readily available to interact with actin and produce force. Additionally, S15D-RLC reconstituted with fibers demonstrated significantly higher maximal isometric force per cross-section of muscle compared with reconstitution with WT-RLC protein. The effects of the phosphomimetic S15D-RLC were compared with those observed for Omecamtiv Mecarbil (OM), a myosin activator shown to bind to the catalytic site of cardiac myosin and increase myocardial contractility. A similar SRX↔DRX equilibrium shift was observed in OM-treated fibers as in S15D-RLC-reconstituted preparations. Additionally, treatment with OM resulted in significantly higher maximal pCa 4 force per cross-section of muscle fibers in both cardiomyopathy models. Our results suggest that both treatments with S15D-RLC and OM may improve the function of myosin motors and cardiac muscle contraction in RCM-ELC and DCM-RLC mice. Full article
(This article belongs to the Special Issue N-Terminal Protein Modifications and Human Diseases)
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11 pages, 8218 KiB  
Article
Brain Region-Specific Differences in Amyloid-β Plaque Composition in 5XFAD Mice
by Angelika Sabine Bader, Marius-Uwe Gnädig, Merle Fricke, Luca Büschgens, Lena Josefine Berger, Hans-Wolfgang Klafki, Thomas Meyer, Olaf Jahn, Sascha Weggen and Oliver Wirths
Life 2023, 13(4), 1053; https://doi.org/10.3390/life13041053 - 20 Apr 2023
Cited by 10 | Viewed by 3384
Abstract
Senile plaques consisting of amyloid-beta (Aβ) peptides are a major pathological hallmark of Alzheimer’s disease (AD). Aβ peptides are heterogeneous regarding the exact length of their amino- and carboxy-termini. Aβ1-40 and Aβ1-42 are often considered to represent canonical “full-length” Aβ species. Using immunohistochemistry, [...] Read more.
Senile plaques consisting of amyloid-beta (Aβ) peptides are a major pathological hallmark of Alzheimer’s disease (AD). Aβ peptides are heterogeneous regarding the exact length of their amino- and carboxy-termini. Aβ1-40 and Aβ1-42 are often considered to represent canonical “full-length” Aβ species. Using immunohistochemistry, we analyzed the distribution of Aβ1-x, Aβx-42 and Aβ4-x species in amyloid deposits in the subiculum, hippocampus and cortex in 5XFAD mice during aging. Overall plaque load increased in all three brain regions, with the subiculum being the area with the strongest relative plaque coverage. In the subiculum, but not in the other brain regions, the Aβ1-x load peaked at an age of five months and decreased thereafter. In contrast, the density of plaques positive for N-terminally truncated Aβ4-x species increased continuously over time. We hypothesize that ongoing plaque remodeling takes place, leading to a conversion of deposited Aβ1-x peptides into Aβ4-x peptides in brain regions with a high Aβ plaque burden. Full article
(This article belongs to the Special Issue N-Terminal Protein Modifications and Human Diseases)
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