Identification of two active functional domains of human adenylate kinase 5

Department of Laboratory Medicine, Karolinska Institute, Huddinge, Sweden.
FEBS letters (Impact Factor: 3.17). 09/2009; 583(17):2872-6. DOI: 10.1016/j.febslet.2009.07.047
Source: PubMed


A full length cDNA that partially corresponded to human adenylate kinase 5 (AK5) was identified and shown to encode for two separate domains. The full length protein could be divided in two distinct functional domains, a previously unidentified domain of 338 amino acids and a second domain of 198 amino acids that corresponded to the protein characterized as AK5, now called AK5p2. The first domain, AK5p1, phosphorylated AMP, CMP, dAMP and dCMP with ATP or GTP as phosphate donors similarly to AK5p2. Our data demonstrate that human AK5 has two separate functional domains and that both have enzymatic activity.

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Available from: Christakis Panayiotou, Feb 10, 2014
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    • "The minor AK6 isoform, also known as transcription factor TAF9 and hCINAP, is localized in the cell nucleus along with AK5 which associates with centrosomes; both isoforms are required for cell growth (Noma 2005; Ren et al. 2005; Zhai et al. 2006). Human AK5 was identified to have two enzymatically active adenylate kinase domains which could catalyze sequential phosphoryl transfer (Solaroli et al. 2009). Another isoform, AK7, has a tissue-specific expression pattern and its activity has been associated with cilia function (Fernandez-Gonzalez et al. 2009). "
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    ABSTRACT: The adenylate kinase isoform network is integral to the cellular energetic system and a major player in AMP metabolic signaling circuits. Critical in energy state monitoring and stress response, the dynamic behavior of the adenylate kinase network in governing intracellular, nuclear, and extracellular nucleotide signaling processes has been increasingly revealed. New adenylate kinase mutations have been identified that cause severe human disease phenotypes such as reticular dysgenesis associated with immunodeficiency and sensorineural hearing loss and primary ciliary dyskinesia characteristic of chronic obstructive pulmonary disease. The adenylate kinase family comprises nine major isoforms (AK1–AK9), and several subforms with distinct intracellular localization and kinetic properties designed to support specific cellular processes ranging from muscle contraction, electrical activity, cell motility, unfolded protein response, and mitochondrial/nuclear energetics. Adenylate kinase and AMP signaling is necessary for energetic communication between mitochondria, myofibrils, and the cell nucleus and for metabolic programming facilitating stem cell cardiac differentiation and mitochondrial network formation. Moreover, it was discovered that during cell cycle, the AK1 isoform translocates to the nucleus and associates with the mitotic spindle to provide energy for cell division. Furthermore, deletion of Ak2 gene is embryonically lethal, indicating critical significance of catalyzed phosphotransfer in the crowded mitochondrial intracristae and subcellular spaces for ATP export and intracellular distribution. Taken together, new evidence highlights the importance of the system-wide adenylate kinase isoform network and adenylate kinase-mediated phosphotransfer and AMP signaling in cellular energetics, metabolic sensing, and regulation of nuclear and cell cycle processes which are critical in tissue homeostasis, renewal, and regeneration.
    Full-text · Chapter · Jan 2014
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    • "AK5 expression is more restricted as compared to most AKs with 51 its expression limited to brain tissue. AK5 is reported to have a 52 cytosolic or both a nuclear and cytosolic expression determined by 53 expression of transcript variants (Solaroli et al., 2009; Van Rompay 54 et al., 1999). As far as AK6 is concerned, fluorescence microscopy 55 revealed a nuclear localization in all tissues investigated whereas 56 the expression of cytosolic AK7 is associated with ciliar function 57 and consequently AK7 expression has been detected in lung, tra- 58 chea, testis and mammary gland tissue (Fernandez-Gonzalez et al., 59 2009). "
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    ABSTRACT: Adenylate kinases regulate adenine nucleotide levels and are present in different intracellular compartments. These enzymes also participate in the activation of pharmacologically active nucleoside and nucleotide analogs. We have in the present study identified the ninth isoform of the adenylate kinase family of enzymes and accordingly named the protein adenylate kinase 9 (AK9). Initially a full-length cDNA of a hypothetical protein containing a predicted adenylate kinase domain was identified and subsequently cloned and expressed in Escherichia coli. The substrate specificity of the recombinant protein showed that the enzyme catalyzed the phosphorylation of AMP, dAMP, CMP and dCMP with ATP as phosphate donor, while only AMP and CMP were phosphorylated when GTP was the phosphate donor. The kinetic parameters of AK9 were determined for AMP, dAMP and CMP with ATP as phosphate donor. Interestingly, in addition to the diphosphate products, a nucleoside diphosphate kinase (NDPK) activity was also present with subsequent triphosphates formed. With ATP or GTP as phosphate donor it was possible to detect the production of ATP, CTP, GTP, UTP, dATP, dCTP, dGTP and TTP as enzymatic products from the corresponding diphosphate substrates. A number of previously characterized adenylate kinases were also tested and found to possess a broad phosphotransferase activity similar to AK9. These enzymes are accordingly suggested to be regarded as nucleoside mono- and diphosphate kinases with catalytic activities possibly determined by local substrate concentrations.
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