Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
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Target Concepts:
Gene/Protein
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Enzyme
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Query: EC:3.1.3.16 (
calcineurin
)
17,112
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
To search for calmodulin (CaM) targets, we performed affinity chromatography purification of a rat brain extract using CaM fused with GST as the affinity ligand. Proteomic analysis was then carried out to identify CaM-binding proteins. In addition to identifying 36 known CaM-binding proteins, including CaM kinases,
calcineurin
, nNOS, the IP(3) receptor, and Ca(2+)-ATPase, we identified an ER transmembrane protein, wolframin [the product of the
Wolfram syndrome
gene (WFS1)] as interacting. A CaM overlay and an immunoprecipitation assay revealed that wolframin is capable of binding the Ca(2+)/CaM complex in vitro and in transfected cells. Surface plasmon resonance analysis and zero-length cross-linking showed that the N-terminal cytoplasmic domain (residues 2-285) of wolframin binds to an equimolar unit of CaM in a Ca(2+)-dependent manner with a K(D) for CaM of 0.15 muM. Various truncation and deletion mutants showed that the Ca(2+)/CaM binding region in wolframin is located from Glu90 to Trp186. Furthermore, we demonstrated that three mutations (Ala127Thr, Ala134Thr, and Arg178Pro) associated with
Wolfram syndrome
completely abolished CaM binding of wolframin. This observation may indicate that CaM binding is important for wolframin function and that impairment of this interaction by mutation contributes to the pathology seen in
Wolfram syndrome
.
...
PMID:Identification and characterization of wolframin, the product of the wolfram syndrome gene (WFS1), as a novel calmodulin-binding protein. 1929 54
CISD2 is a causative gene associated with
Wolfram syndrome
(
WFS
). However, it remains a mystery as to how the loss of CISD2 causes metabolic defects in patients with
WFS
. Investigation on the role played by Cisd2 in specific cell types may help us to resolve these underlying mechanisms. White adipose tissue (WAT) is central to the maintenance of energy metabolism and glucose homeostasis in humans. In this study, adipocyte-specific Cisd2 knockout (KO) mice showed impairment in the development of epididymal WAT (eWAT) in the cell autonomous manner. A lack of Cisd2 caused defects in the biogenesis and function of mitochondria during differentiation of adipocytes in vitro. Insulin-stimulated glucose uptake and secretion of adiponectin by the Cisd2 KO adipocytes were decreased. Moreover, Cisd2 deficiency increased the cytosolic level of Ca(2+) and induced Ca(2+)-
calcineurin
-dependent signaling that inhibited adipogenesis. Importantly, Cisd2 was found to interact with Gimap5 on the mitochondrial and ER membranes and thereby modulate mitochondrial Ca(2+) uptake associated with the maintenance of intracellular Ca(2+) homeostasis in adipocytes. Thus, it would seem that Cisd2 plays an important role in intracellular Ca(2+) homeostasis, which is required for the differentiation and functioning of adipocytes as well as the regulation of glucose homeostasis in mice.
...
PMID:Cisd2 modulates the differentiation and functioning of adipocytes by regulating intracellular Ca2+ homeostasis. 2483 25
The origin of eukaryotes was marked by the emergence of several novel subcellular systems. One such is the calcium (Ca
2+
)-stores system of the endoplasmic reticulum, which profoundly influences diverse aspects of cellular function including signal transduction, motility, division, and biomineralization. We use comparative genomics and sensitive sequence and structure analyses to investigate the evolution of this system. Our findings reconstruct the core form of the Ca
2+
-stores system in the last eukaryotic common ancestor as having at least 15 proteins that constituted a basic system for facilitating both Ca
2+
flux across endomembranes and Ca
2+
-dependent signaling. We present evidence that the key EF-hand Ca
2+
-binding components had their origins in a likely bacterial symbiont other than the mitochondrial progenitor, whereas the
protein phosphatase
subunit of the ancestral
calcineurin
complex was likely inherited from the asgard archaeal progenitor of the stem eukaryote. This further points to the potential origin of the eukaryotes in a Ca
2+
-rich biomineralized environment such as stromatolites. We further show that throughout eukaryotic evolution there were several acquisitions from bacteria of key components of the Ca
2+
-stores system, even though no prokaryotic lineage possesses a comparable system. Further, using quantitative measures derived from comparative genomics we show that there were several rounds of lineage-specific gene expansions, innovations of novel gene families, and gene losses correlated with biological innovation such as the biomineralized molluscan shells, coccolithophores, and animal motility. The burst of innovation of new genes in animals included the wolframin protein associated with
Wolfram syndrome
in humans. We show for the first time that it contains previously unidentified Sel1, EF-hand, and OB-fold domains, which might have key roles in its biochemistry.
...
PMID:Functional Innovation in the Evolution of the Calcium-Dependent System of the Eukaryotic Endoplasmic Reticulum. 3211 48
