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PloS One 2022TMPRSS6 is a type II transmembrane serine protease involved in iron homeostasis expressed as 4 isoforms in humans. TMPRSS6 isoform 2 downregulates hepcidin production by...
TMPRSS6 is a type II transmembrane serine protease involved in iron homeostasis expressed as 4 isoforms in humans. TMPRSS6 isoform 2 downregulates hepcidin production by cleaving hemojuvelin and other surface proteins of hepatocytes. The functions of catalytically impaired isoforms 3 and 4 are still unknown. Here we demonstrate that TMPRSS6 isoforms 3 and 4 reduce the proteolytic activity of isoform 2 and uncover the ability of isoforms to interact. Moreover, we identified 49 potential protein partners common to TMPRSS6 isoforms, including TfR1, known to be involved in iron regulation. By co-expressing TMPRSS6 and TfR1, we show that TfR1 is cleaved and shed from the cell surface. Further, we demonstrate that TMPRSS6 isoforms 3 and 4 behave as dominant negative.
Topics: Cell Membrane; Hepcidins; Humans; Iron; Membrane Proteins; Protein Isoforms; Serine Endopeptidases
PubMed: 36044454
DOI: 10.1371/journal.pone.0273825 -
International Journal of Molecular... Nov 2016Although it is one of the most studied proteins, p53 continues to be an enigma. This protein has numerous biological functions, possesses intrinsically disordered... (Review)
Review
Although it is one of the most studied proteins, p53 continues to be an enigma. This protein has numerous biological functions, possesses intrinsically disordered regions crucial for its functionality, can form both homo-tetramers and isoform-based hetero-tetramers, and is able to interact with many binding partners. It contains numerous posttranslational modifications, has several isoforms generated by alternative splicing, alternative promoter usage or alternative initiation of translation, and is commonly mutated in different cancers. Therefore, p53 serves as an important illustration of the protein structure-function continuum concept, where the generation of multiple proteoforms by various mechanisms defines the ability of this protein to have a multitude of structurally and functionally different states. Considering p53 in the light of a proteoform-based structure-function continuum represents a non-canonical and conceptually new contemplation of structure, regulation, and functionality of this important protein.
Topics: Alternative Splicing; Humans; Intrinsically Disordered Proteins; Models, Molecular; Mutation; Protein Binding; Protein Conformation; Protein Isoforms; Protein Processing, Post-Translational; Tumor Suppressor Protein p53
PubMed: 27834926
DOI: 10.3390/ijms17111874 -
Frontiers in Immunology 2020C-reactive protein (CRP) is a widely known, hepatically synthesized protein whose blood levels change rapidly and pronouncedly in response to any tissue damaging event... (Review)
Review
C-reactive protein (CRP) is a widely known, hepatically synthesized protein whose blood levels change rapidly and pronouncedly in response to any tissue damaging event associated with an inflammatory response. The synthesis and secretion of CRP is stimulated by interleukin-6, an early pleiotropic cytokine released by macrophages, endothelial, and other cells that are activated when localized normal tissue structures are compromised by trauma or disease. Serum CRP levels can change rapidly and robustly from 10-100-fold within 6-72 h of any tissue damaging event. Elevated blood levels correlate with the onset and extent of both activated inflammation and the acute phase biochemical response to the tissue insult. Because its functional bioactivity as the prototypic acute phase reactant has eluded clear definition for decades, diagnosticians of various conditions and diseases use CRP blood levels as a simple index for ongoing inflammation. In many pathologies, which involves many different tissues, stages of disease, treatments, and responses to treatments, its interpretive diagnostic value requires a deeper understanding of the localized tissue processes and events that contribute signals which regulate protective or pathological host defense bioactivities. This report presents concepts that describe how local tissue activation events can lead to a non-proteolytic, conformational rearrangement of CRP into a unique isoform with distinctive solubility, antigenicity, binding reactivities and bioactivities from that protein widely known and measured in serum. By describing factors that control the expression, tissue localization, half-life and pro-inflammatory amplification activity of this CRP isoform, a unifying explanation for the diagnostic significance of CRP measurement in disease is advanced.
Topics: C-Reactive Protein; Disease Progression; Humans; Inflammation; Protein Conformation; Protein Isoforms
PubMed: 33013897
DOI: 10.3389/fimmu.2020.02126 -
Trends in Biochemical Sciences Feb 2017Alternative splicing is commonly believed to be a major source of cellular protein diversity. However, although many thousands of alternatively spliced transcripts are... (Review)
Review
Alternative splicing is commonly believed to be a major source of cellular protein diversity. However, although many thousands of alternatively spliced transcripts are routinely detected in RNA-seq studies, reliable large-scale mass spectrometry-based proteomics analyses identify only a small fraction of annotated alternative isoforms. The clearest finding from proteomics experiments is that most human genes have a single main protein isoform, while those alternative isoforms that are identified tend to be the most biologically plausible: those with the most cross-species conservation and those that do not compromise functional domains. Indeed, most alternative exons do not seem to be under selective pressure, suggesting that a large majority of predicted alternative transcripts may not even be translated into proteins.
Topics: Alternative Splicing; Exons; Protein Isoforms; Proteome; Proteomics
PubMed: 27712956
DOI: 10.1016/j.tibs.2016.08.008 -
Seminars in Cell & Developmental Biology Jun 2020Actin is one of the most abundant and essential intracellular proteins that mediates nearly every form of cellular movement and underlies such key processes as... (Review)
Review
Actin is one of the most abundant and essential intracellular proteins that mediates nearly every form of cellular movement and underlies such key processes as embryogenesis, tissue integrity, cell division and contractility of all types of muscle and non-muscle cells. In mammals, actin is represented by six isoforms, which are encoded by different genes but produce proteins that are 95-99 % identical to each other. The six actin genes have vastly different functions in vivo, and the small amino acid differences between the proteins they encode are rigorously maintained through evolution, but the underlying differences behind this distinction, as well as the importance of specific amino acid sequences for each actin isoform, are not well understood. This review summarizes different levels of actin isoform-specific regulation in cellular and developmental processes, starting with the nuclear actin's role in transcription, and covering the gene-level, mRNA-level, and protein-level regulation, with a special focus on mammalian actins in non-muscle cells.
Topics: Actins; Animals; Cells; Growth and Development; Humans; Protein Isoforms
PubMed: 32001148
DOI: 10.1016/j.semcdb.2019.12.003 -
Angewandte Chemie (International Ed. in... May 2021The 90 kDa heat shock protein (Hsp90) is a molecular chaperone that processes nascent polypeptides into their biologically active conformations. Many of these proteins...
The 90 kDa heat shock protein (Hsp90) is a molecular chaperone that processes nascent polypeptides into their biologically active conformations. Many of these proteins contribute to the progression of cancer, and consequently, inhibition of the Hsp90 protein folding machinery represents an innovative approach toward cancer chemotherapy. However, clinical trials with Hsp90 N-terminal inhibitors have encountered deleterious side effects and toxicities, which appear to result from the pan-inhibition of all four Hsp90 isoforms. Therefore, the development of isoform-selective Hsp90 inhibitors is sought to delineate the pathological role played by each isoform. Herein, we describe a structure-based approach that was used to design the first Hsp90α-selective inhibitors, which exhibit >50-fold selectivity versus other Hsp90 isoforms.
Topics: Antineoplastic Agents; HSP90 Heat-Shock Proteins; Humans; Neoplasms; Protein Isoforms
PubMed: 33621416
DOI: 10.1002/anie.202015422 -
Chemical Society Reviews Jul 2008Histone deacetylase (HDAC) proteins are transcription regulators linked to cancer. As a result, multiple small molecule HDAC inhibitors are in various phases of clinical... (Review)
Review
Histone deacetylase (HDAC) proteins are transcription regulators linked to cancer. As a result, multiple small molecule HDAC inhibitors are in various phases of clinical trials as anti-cancer drugs. The majority of HDAC inhibitors non-selectively influence the activities of eleven human HDAC isoforms, which are divided into distinct classes. This tutorial review focuses on the recent progress toward the identification of class-selective and isoform-selective HDAC inhibitors. The emerging trends suggest that subtle differences in the active sites of the HDAC isoforms can be exploited to dictate selectivity.
Topics: Antineoplastic Agents; Binding Sites; Cell Proliferation; Drug Design; Enzyme Inhibitors; Histone Deacetylase Inhibitors; Histone Deacetylases; Humans; Hydroxamic Acids; Protein Isoforms; Tumor Cells, Cultured; Vorinostat
PubMed: 18568166
DOI: 10.1039/b703830p -
The American Journal of Pathology Oct 2020Studies of lysosome associated protein transmembrane 4B (LAPTM4B) have mainly focused on the 35-kDa isoform and its association with poor prognosis in cancers. Here, by...
Studies of lysosome associated protein transmembrane 4B (LAPTM4B) have mainly focused on the 35-kDa isoform and its association with poor prognosis in cancers. Here, by employing a novel monoclonal antibody, the authors found that the 24-kDa LAPTM4B isoform predominated in most, both healthy and malignant, human cells and tissues studied. LAPTM4B-24 lacks the extreme N-terminus and, contrary to LAPTM4B-35, failed to promote cell migration. The endogenous LAPTM4B-24 protein was subject to rapid turnover with a t of approximately 1 hour. The protein was degraded by both lysosomal and proteasomal pathways, and its levels were increased by the availability of nutrients and lysosomal ceramide. These findings underscore the pathophysiological relevance of the LAPTM4B-24 isoform and identify it as a dynamically regulated effector in lysosomal nutrient signaling.
Topics: Cell Movement; Ceramides; Humans; Lysosomes; Membrane Proteins; Oncogene Proteins; Protein Isoforms; Signal Transduction; Transcription Factors
PubMed: 32679228
DOI: 10.1016/j.ajpath.2020.07.003 -
The International Journal of... Aug 2012While early 1990s reports showed the phosphorylation pattern of fetal tau protein to be similar to that of tau in paired helical filaments (PHF) in Alzheimer's disease... (Review)
Review
While early 1990s reports showed the phosphorylation pattern of fetal tau protein to be similar to that of tau in paired helical filaments (PHF) in Alzheimer's disease (AD), neither the molecular mechanisms of the transient developmental hyperphosphorylation of tau nor reactivation of the fetal plasticity due to re-expression of fetal protein kinases in the aging and AD human brain have been sufficiently investigated. Here, we summarize the current knowledge on fetal tau, adding new data on the specific patterns of tau protein and mRNA expression in the developing human brain as well as on change in tau phosphorylation in the perforant pathway after entorhinal cortex lesion in mice. As fetal tau isoform does not form PHF even in a highly phosphorylated state, understanding its expression and post-translational modifications represents an important avenue for future research towards the development of AD treatment and prevention.
Topics: Alzheimer Disease; Animals; Brain; Fetus; Gene Expression Regulation, Developmental; Humans; Mice; Phosphorylation; Protein Isoforms; tau Proteins
PubMed: 22595282
DOI: 10.1016/j.biocel.2012.05.001 -
Cells Apr 2022Vascular endothelial growth factor A (VEGF-A) is a secreted protein that stimulates angiogenesis in response to hypoxia. Under hypoxic conditions, a non-canonical long...
Vascular endothelial growth factor A (VEGF-A) is a secreted protein that stimulates angiogenesis in response to hypoxia. Under hypoxic conditions, a non-canonical long isoform called is concomitantly expressed with . Once translated, L-VEGF is proteolytically cleaved to generate N-VEGF and VEGF-A. Interestingly, while VEGF-A is secreted and affects the surrounding cells, N-VEGF is mobilized to the nucleus. This suggests that N-VEGF participates in transcriptional response to hypoxia. In this study, we performed a series of complementary experiments to examine the functional role of N-VEGF. Strikingly, we found that the mere expression of N-VEGF followed by its hypoxia-independent mobilization to the nucleus was sufficient to induce key genes associated with angiogenesis, such as isoforms, as well as genes associated with cell survival under hypoxia. Complementarily, when was genetically depleted, key hypoxia-induced genes were downregulated and cells were significantly susceptible to hypoxia-mediated apoptosis. This is the first report of N-VEGF serving as an autoregulatory arm of VEGF-A. Further experiments will be needed to determine the role of N-VEGF in cancer and embryogenesis.
Topics: Apoptosis; Cell Hypoxia; Humans; Hypoxia; Neovascularization, Pathologic; Protein Isoforms; Vascular Endothelial Growth Factor A
PubMed: 35455969
DOI: 10.3390/cells11081289