Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.6.1.3 (ATPase)
 65,361 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The RNA helicase UPF1 is a key component of the nonsense mediated mRNA decay (NMD) pathway. Previous X-ray crystal structures of UPF1 elucidated the molecular mechanisms of its catalytic activity and regulation. In this study, we examine features of the UPF1 core and identify a structural element that adopts different conformations in the various nucleotide- and RNA-bound states of UPF1. We demonstrate, using biochemical and single molecule assays, that this structural element modulates UPF1 catalytic activity and thereby refer to it as the regulatory loop. Interestingly, there are two alternatively spliced isoforms of UPF1 in mammals which differ only in the lengths of their regulatory loops. The loop in isoform 1 (UPF11) is 11 residues longer than that of isoform 2. We find that this small insertion in UPF11 leads to a two-fold increase in its translocation and ATPase activities. To determine the mechanistic basis of this differential catalytic activity, we have determined the X-ray crystal structure of the helicase core of UPF11 in its apo-state. Our results point toward a novel mechanism of regulation of RNA helicases, wherein alternative splicing leads to subtle structural rearrangements within the protein that are critical to modulate enzyme movements and catalytic activity.
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PMID:A conserved structural element in the RNA helicase UPF1 regulates its catalytic activity in an isoform-specific manner. 2937 13

The plasma membrane Ca2+ ATPases (PMCAs) are responsible for the clearance of Ca2+ out of cells after intracellular Ca2+ transients. Cooperating with Na+/Ca2+ exchangers (NCXs) and Ca2+ buffering proteins, PMCAs play an essential role in maintaining the long-term cellular Ca2+ homeostasis. The plasma membrane Ca2+ ATPase was first discovered in red blood cell membrane about 50 years ago, and then other PMCA isoforms and alternatively spliced variants had been identified from different tissues and different developmental stages, revealing a surprising complexity of the PMCA family. In mammals, there are four PMCA isoforms encoded by four distinct genes. Isoform 1 and 4 are found in virtually all tissues, whereas isoform 2 and 3 are primarily expressed in excitable cells such as neurons and myocytes. Perturbation of PMCAs function has been implicated in a variety of diseases and disorders, including hearing loss, ataxia, paraplegia, and infertility. Here, we would like to review the recent progresses in the study of the PMCAs and related disorders, in particular how these pathological conditions help us to gain an in-depth insight into the function of PMCAs and their contribution in the regulation of Ca2+ signaling network.
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PMID:The Plasma Membrane Calcium ATPases in Calcium Signaling Network. 2966 80

The human IL22RA2 gene co-produces three protein isoforms in dendritic cells [IL-22 binding protein isoform-1 (IL-22BPi1), IL-22BPi2, and IL-22BPi3]. Two of these, IL-22BPi2 and IL-22BPi3, are capable of neutralizing the biological activity of IL-22. The function of IL-22BPi1, which differs from IL-22BPi2 through an in-frame 32-amino acid insertion provided by an alternatively spliced exon, remains unknown. Using transfected human cell lines, we demonstrate that IL-22BPi1 is secreted detectably, but at much lower levels than IL-22BPi2, and unlike IL-22BPi2 and IL-22BPi3, is largely retained in the endoplasmic reticulum (ER). As opposed to IL-22BPi2 and IL-22BPi3, IL-22BPi1 is incapable of neutralizing or binding to IL-22 measured in bioassay or assembly-induced IL-22 co-folding assay. We performed interactome analysis to disclose the mechanism underlying the poor secretion of IL-22BPi1 and identified GRP78, GRP94, GRP170, and calnexin as main interactors. Structure-function analysis revealed that, like IL-22BPi2, IL-22BPi1 binds to the substrate-binding domain of GRP78 as well as to the middle domain of GRP94. Ectopic expression of wild-type GRP78 enhanced, and ATPase-defective GRP94 mutant decreased, secretion of both IL-22BPi1 and IL-22BPi2, while neither of both affected IL-22BPi3 secretion. Thus, IL-22BPi1 and IL-22BPi2 are bona fide clients of the ER chaperones GRP78 and GRP94. However, only IL-22BPi1 activates an unfolded protein response (UPR) resulting in increased protein levels of GRP78 and GRP94. Cloning of the IL22RA2 alternatively spliced exon into an unrelated cytokine, IL-2, bestowed similar characteristics on the resulting protein. We also found that CD14++/CD16+ intermediate monocytes produced a higher level of IL22RA2 mRNA than classical and non-classical monocytes, but this difference disappeared in immature dendritic cells (moDC) derived thereof. Upon silencing of IL22RA2 expression in moDC, GRP78 levels were significantly reduced, suggesting that native IL22RA2 expression naturally contributes to upregulating GRP78 levels in these cells. The IL22RA2 alternatively spliced exon was reported to be recruited through a single mutation in the proto-splice site of a Long Terminal Repeat retrotransposon sequence in the ape lineage. Our work suggests that positive selection of IL-22BPi1 was not driven by IL-22 antagonism as in the case of IL-22BPi2 and IL-22BPi3, but by capacity for induction of an UPR response.
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PMID:Long Interleukin-22 Binding Protein Isoform-1 Is an Intracellular Activator of the Unfolded Protein Response. 3061 94

Actinic keratosis, Bowen's disease and cutaneous squamous cell carcinoma (cSCC) are heterogeneous keratinocytic skin lesions. Biomarkers that can accurately stratify these lesion types are needed to support a new paradigm of personalized and precise management of skin neoplasia. In this paper, we used a data independent acquisition proteomics workflow, sequential window acquisition of all theoretical mass spectra, to analyze formalin-fixed paraffin-embedded samples of normal skin and keratinocytic skin lesions, including well-differentiated, moderately differentiated and poorly differentiated cSCC lesions. We quantified 3,574 proteins across the 93 samples studied. Differential abundance analysis identified 19, 5, and 6 protein markers exclusive to actinic keratosis, Bowen's disease and cSCC lesions, respectively. Among cSCC lesions of various levels of tumor differentiation, 118, 230, and 17 proteins showed a potential as biomarkers of well-differentiated, moderately differentiated and poorly differentiated cSCC lesions, respectively. Bioinformatics analysis revealed that actinic keratosis and cSCC lesions were associated with decreased apoptosis, and Bowen's disease lesions with over-representation of the DNA damage repair pathway. Differential expression of alternatively spliced FGFR2, Rho guanosine triphosphatase signaling, and RNA metabolism proteins were associated with the level of cSCC tumor differentiation. Proteome profiles also separated keratinocytic skin lesion subtypes on principal components analysis. Overall, protein markers have excellent potential to discriminate keratinocytic skin lesion subtypes and facilitate new diagnostic and therapeutic strategies.
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PMID:Data Independent Acquisition Proteomic Analysis Can Discriminate between Actinic Keratosis, Bowen's Disease, and Cutaneous Squamous Cell Carcinoma. 3125 17

ATP11C, a member of the P4-ATPase family, is a major phosphatidylserine (PS)-flippase located at the plasma membrane. ATP11C deficiency causes a defect in B-cell maturation, anemia and hyperbilirubinemia. Although there are several alternatively spliced variants derived from the ATP11C gene, the functional differences between them have not been considered. Here, we compared and characterized three C-terminal spliced forms (we designated as ATP11C-a, ATP11C-b and ATP11C-c), with respect to their expression patterns in cell types and tissues, and their subcellular localizations. We had previously shown that the C-terminus of ATP11C-a is critical for endocytosis upon PKC activation. Here, we found that ATP11C-b and ATP11C-c did not undergo endocytosis upon PKC activation. Importantly, we also found that ATP11C-b localized to a limited region of the plasma membrane in polarized cells, whereas ATP11C-a was distributed on the entire plasma membrane in both polarized and non-polarized cells. Moreover, we successfully identified LLXY residues within the ATP11C-b C-terminus as a critical motif for the polarized localization. These results suggest that the ATP11C-b regulates PS distribution in distinct regions of the plasma membrane in polarized cells.
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PMID:The cytoplasmic C-terminal region of the ATP11C variant determines its localization at the polarized plasma membrane. 3137 88


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