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Computational Simulations to Predict Creatine Kinase-Associated Factors: Protein-Protein Interaction Studies of Brain and Muscle Types of Creatine Kinases  [PDF]
Wei-Jiang Hu,Sheng-Mei Zhou,Joshua SungWoo Yang,Fan-Guo Meng
Enzyme Research , 2011, DOI: 10.4061/2011/328249
Abstract: Creatine kinase (CK; EC 2.7.3.2) is related to several skin diseases such as psoriasis and dermatomyositis. CK is important in skin energy homeostasis because it catalyzes the reversible transfer of a phosphoryl group from MgATP to creatine. In this study, we predicted CK binding proteins via the use of bioinformatic tools such as protein-protein interaction (PPI) mappings and suggest the putative hub proteins for CK interactions. We obtained 123 proteins for brain type CK and 85 proteins for muscle type CK in the interaction networks. Among them, several hub proteins such as NFKB1, FHL2, MYOC, and ASB9 were predicted. Determination of the binding factors of CK can further promote our understanding of the roles of CK in physiological conditions. 1. Introduction Creatine kinase (CK) (ATP: creatine kinase N-phosphotransferase, EC 2.7.3.2) is thought to be crucial for intracellular transport and the storage of high energy phosphate because it catalyzes the reversible transfer of a phosphoryl group from MgATP to creatine, which leads to the creation of phosphocreatine and MgADP [1]. CK plays an important role in the cellular energy metabolism of vertebrates, and it is widely distributed in tissues that require a lot of energy [2]. Several types of CK are expressed in various tissues: the muscle and brain types of CK are the most common, and three different isoenzymes that include CK-MM (the muscle type homodimer), CK-BB (the brain type homodimer), and CK-MB (the muscle plus brain type heterodimer) originate from these two common types. CK is an important serum marker for myocardial infarction. Various types of CKs (the muscle, brain, and mitochondrial types) are thought to be important not only in the diagnosis of myocardial infarction, cardiac hypertrophy, and muscular dystrophy but also for studies of some other serious diseases, including Alzheimer’s disease, Parkinson's disease, and psoriasis [3–8]. CK-BB is associated with several pathologies, including neurodegenerative and age-related diseases. Recently, Chang et al. [9] reported an important role for CK-BB in osteoclast-mediated bone resorption, which was found using a proteomics approach. They found that CK-BB is greatly increased during osteoclastogenesis and suggested that it represents a potential target for antiresorptive drug development. CK-BB interacts with the potassium-chloride cotransporter 3, which is involved in the pathophysiology of hereditary motor and sensory neuropathy with agenesis of the corpus callosum [10]. Previous studies [11, 12] have reported that CK-BB is involved in
Administration of Harmine and Imipramine Alters Creatine Kinase and Mitochondrial Respiratory Chain Activities in the Rat Brain  [PDF]
Gislaine Z. Réus,Roberto B. Stringari,Cinara L. Gon?alves,Giselli Scaini,Milena Carvalho-Silva,Gabriela C. Jeremias,Isabela C. Jeremias,Gabriela K. Ferreira,Emílio L. Streck,Jaime E. Hallak,Ant?nio W. Zuardi,José A. Crippa,Jo?o Quevedo
Depression Research and Treatment , 2012, DOI: 10.1155/2012/987397
Abstract: The present study evaluated mitochondrial respiratory chain and creatine kinase activities after administration of harmine (5, 10, and 15?mg/kg) and imipramine (10, 20, and 30?mg/kg) in rat brain. After acute treatment occurred an increase of creatine kinase in the prefrontal with imipramine (20 and 30?mg/kg) and harmine in all doses, in the striatum with imipramine (20 and 30?mg/kg) and harmine (5 and 10?mg/kg); harmine (15?mg/kg) decreased creatine kinase. In the chronic treatment occurred an increase of creatine kinase with imipramine (20?mg/kg), harmine (5?mg/kg) in the prefrontal with imipramine (20 and 30?mg/kg) and harmine (5 and 10?mg/kg) in the striatum. In the acute treatment, the complex I increased in the prefrontal with harmine (15?mg/kg) and in the striatum with harmine (10?mg/kg); the complex II decreased with imipramine (20 and 30?mg/kg) in the striatum; the complex IV increased with imipramine (30?mg/kg) in the striatum. In the chronic treatment, the complex I increased with harmine (5?mg/kg) in the prefrontal; the complex II increased with imipramine (20?mg/kg) in the prefrontal; the complex IV increased with harmine (5?mg/kg) in the striatum. Finally, these findings further support the hypothesis that harmine and imipramine could be involved in mitochondrial function. 1. Introduction For more than 30 years, it has been theorized that levels of monoamines, such as serotonin, norepinephrine, and dopamine, are generally low in the brain during untreated major depressive episodes [1]. In fact, the clinically used antidepressants increase the extracellular concentrations of monoamines, serotonin, or norepinephrine either by inhibiting their reuptake from the synapse or by blocking their degradation by inhibiting monoamine oxidase [2–4]. The β-carboline harmine is present in plants, such as Peganum harmala and Banisteriopsis caap, which are used for ritual and medicinal preparations [5]. Also, ingestion of Ayahuasca, which contains harmine in its composition improved psychometric measures of panic and hopelessness in humans [6]. Recently, a growing body of evidence has indicated that harmine presents antidepressant-like actions in rodents subjected to an animal model of depression [7–10]. In addition, studies have demonstrated that harmine interacts with monoamine oxidase A (MAO-A) [11] and several cell-surface receptors, including serotonin receptor 2A (5-HT2A) [12], which are involved in antidepressant pharmacotherapy [13]. The creatine/phosphocreatine/CK system is important for normal to maintain the energy homeostasis [14, 15] exerting
FUS Interacts with HSP60 to Promote Mitochondrial Damage  [PDF]
Jianwen Deng?,Mengxue Yang?,Yanbo Chen?,Xiaoping Chen?,Jianghong Liu?,Shufeng Sun?,Haipeng Cheng?,Yang Li?,Eileen H. Bigio?,Marsel Mesulam
PLOS Genetics , 2015, DOI: 10.1371/journal.pgen.1005357
Abstract: FUS-proteinopathies, a group of heterogeneous disorders including ALS-FUS and FTLD-FUS, are characterized by the formation of inclusion bodies containing the nuclear protein FUS in the affected patients. However, the underlying molecular and cellular defects remain unclear. Here we provide evidence for mitochondrial localization of FUS and its induction of mitochondrial damage. Remarkably, FTLD-FUS brain samples show increased FUS expression and mitochondrial defects. Biochemical and genetic data demonstrate that FUS interacts with a mitochondrial chaperonin, HSP60, and that FUS translocation to mitochondria is, at least in part, mediated by HSP60. Down-regulating HSP60 reduces mitochondrially localized FUS and partially rescues mitochondrial defects and neurodegenerative phenotypes caused by FUS expression in transgenic flies. This is the first report of direct mitochondrial targeting by a nuclear protein associated with neurodegeneration, suggesting that mitochondrial impairment may represent a critical event in different forms of FUS-proteinopathies and a common pathological feature for both ALS-FUS and FTLD-FUS. Our study offers a potential explanation for the highly heterogeneous nature and complex genetic presentation of different forms of FUS-proteinopathies. Our data also suggest that mitochondrial damage may be a target in future development of diagnostic and therapeutic tools for FUS-proteinopathies, a group of devastating neurodegenerative diseases.
Tim50a, a nuclear isoform of the mitochondrial Tim50, interacts with proteins involved in snRNP biogenesis
Hongzhi Xu, Z Brad Somers, Melvin L Robinson, Michael D Hebert
BMC Cell Biology , 2005, DOI: 10.1186/1471-2121-6-29
Abstract: In this report, we identify a minor isoform of the mitochondrial Tim50, Tim50a, as a coilin interacting protein. The Tim50a transcript can be detected in some cancer cell lines and normal brain tissue. The Tim50a protein differs only from Tim50 in that it contains an additional 103 aa N-terminal to the translation start of Tim50. Importantly, a putative nuclear localization signal is found within these 103 residues. In contrast to Tim50, which localizes to the cytoplasm and mitochondria, Tim50a is strictly nuclear and is enriched in speckles with snRNPs. In addition to coilin, Tim50a interacts with snRNPs and SMN. Competition binding experiments demonstrate that coilin competes with Sm proteins of snRNPs and SMN for binding sites on Tim50a.Tim50a may play a role in snRNP biogenesis given its cellular localization and protein interaction characteristics. We hypothesize that Tim50a takes part in the release of snRNPs and SMN from the CB.The biogenesis of most spliceosomal small nuclear ribonucleoproteins (snRNPs) is complicated and requires both cytoplasmic and nuclear maturation steps [1-3]. For example, the spliceosomal small nuclear RNAs (snRNAs) of Ul, U2, U4 and U5 snRNPs are synthesized by RNA polymerase II and may traffic through specific subnuclear domains before being exported to the cytoplasm [1,3]. In the cytoplasm, a septet of Sm proteins (B/B', Dl, D2, D3, E, F, G) binds the Sm motif of the snRNA under the control of the Survival of Motor Neurons (SMN) protein complex. Mutations in the SMN protein cause the neurodegenerative disorder Spinal Muscular Atrophy [4,5]. After the Sm core has been assembled onto the snRNA, the snRNA is subject to further processing, followed by import back into the nucleus; again with the help of the SMN complex [1,5-8].Upon nuclear re-entry, newly assembled Ul, U2, U4 and U5 snRNPs first localize to a subnuclear domain known as the Cajal body [9]. In the Cajal body (CB), the snRNA component of the snRNP is subjected to pseudour
CREATINE KINASE: STRUCTURE AND FUNCTION  [PDF]
Ana Maria Teixeira,Grasiely F. Borges
Brazilian Journal of Biomotricity , 2012,
Abstract: TEIXEIRA, A. M.; BORGES, G. F. Creatine kinase: structure and function. Brazilian Journal of Biomotricity. v. 6, n. 2, p. 53-65, 2012. Found in all vertebrates, creatine kinase (CK) is a member of the phosphagen kinase family and catalyzes the reversible phosphotransfer between the ATP/ADP and Creatine/Phosphocreatine systems. CK is highly expressed in excitable tissues that require large energy fluxes and plays a significant role in the energy homeostasis of these tissue cells. The creatine kinase reaction was first identified in 1934 by K Lohman in the muscle tissue and it has undergone intensive investigation for over 80 years. The enzyme is of clinical importance and its levels are routinely used as an indicator of acute myocardial infarction. There are four major CK isoforms, which are named according to their tissue distribution or subcellular localization: two tissue (muscle or brain) cytosolic and two mitochondrial, which form dimers and octamers, respectively. In this paper we will include a brief summary of the history of the detection of creatine kinases isoforms, their main structural features, physical and catalitic properties and multiple functions such as an energy buffering function, metabolic regulatory functions and the energy transport function.
A cyclopalladated complex interacts with mitochondrial membrane thiol-groups and induces the apoptotic intrinsic pathway in murine and cisplatin-resistant human tumor cells
Fabiana A Serrano, Alisson L Matsuo, Priscila T Monteforte, Alexandre Bechara, Soraya S Smaili, Débora P Santana, Tiago Rodrigues, Felipe V Pereira, Luis S Silva, Joel Machado, Edson L Santos, Jo?o B Pesquero, Rafael M Martins, Luiz R Travassos, Antonio CF Caires, Elaine G Rodrigues
BMC Cancer , 2011, DOI: 10.1186/1471-2407-11-296
Abstract: B16F10-Nex2 cells were treated in vitro with C7a in the presence/absence of DTT, and several parameters related to apoptosis induction were evaluated. Preclinical studies were performed, and mice were endovenously inoculated with B16F10-Nex2 cells, intraperitoneally treated with C7a, and lung metastatic nodules were counted. The cytotoxic effects and the respiratory metabolism were also determined in human tumor cell lines treated in vitro with C7a.Cyclopalladated complex interacts with thiol groups on the mitochondrial membrane proteins, causes dissipation of the mitochondrial membrane potential, and induces Bax translocation from the cytosol to mitochondria, colocalizing with a mitochondrial tracker. C7a also induced an increase in cytosolic calcium concentration, mainly from intracellular compartments, and a significant decrease in the ATP levels. Activation of effector caspases, chromatin condensation and DNA degradation, suggested that C7a activates the apoptotic intrinsic pathway in murine melanoma cells. In the preclinical studies, the C7a complex protected against murine metastatic melanoma and induced death in several human tumor cell lineages in vitro, including cisplatin-resistant ones. The mitochondria-dependent cell death was also induced by C7a in human tumor cells.The cyclopalladated C7a complex is an effective chemotherapeutic anticancer compound against primary and metastatic murine and human tumors, including cisplatin-resistant cells, inducing apoptotic cell death via the intrinsic pathway.The incidence of malignant melanoma is rising and has not been associated with significantly better therapeutic options. Treatments of choice for the systemic therapy of metastatic lesions have used mono-chemo and immunotherapy, both with low records of clinical response. Even the combination of several chemotherapeutic compounds and the use of biochemotherapy protocols were not able to improve the overall survival of patients [reviewed in [1] and [2]]. In conse
The Pseudophosphatase MK-STYX Physically and Genetically Interacts with the Mitochondrial Phosphatase PTPMT1  [PDF]
Natalie M. Niemi, Juliana L. Sacoman, Laura M. Westrate, L. Alex Gaither, Nathan J. Lanning, Katie R. Martin, Jeffrey P. MacKeigan
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0093896
Abstract: We previously performed an RNA interference (RNAi) screen and found that the knockdown of the catalytically inactive phosphatase, MK-STYX [MAPK (mitogen-activated protein kinase) phospho-serine/threonine/tyrosine-binding protein], resulted in potent chemoresistance. Our follow-up studies demonstrated that knockdown of MK-STYX prevents cells from undergoing apoptosis through a block in cytochrome c release, but that MK-STYX does not localize proximal to the molecular machinery currently known to control this process. In an effort to define its molecular mechanism, we utilized an unbiased proteomics approach to identify proteins that interact with MK-STYX. We identified the mitochondrial phosphatase, PTPMT1 (PTP localized to mitochondrion 1), as the most significant and unique interaction partner of MK-STYX. We previously reported that knockdown of PTPMT1, an important component of the cardiolipin biosynthetic pathway, is sufficient to induce apoptosis and increase chemosensitivity. Accordingly, we hypothesized that MK-STYX and PTPMT1 interact and serve opposing functions in mitochondrial-dependent cell death. We confirmed that MK-STYX and PTPMT1 interact in cells and, importantly, found that MK-STYX suppresses PTPMT1 catalytic activity. Furthermore, we found that knockdown of PTPMT1 resensitizes MK-STYX knockdown cells to chemotherapeutics and restores the ability to release cytochrome c. Taken together, our data support a model in which MK-STYX controls apoptosis by negatively regulating PTPMT1. Given the important role of PTPMT1 in the production of cardiolipin and other phospholipids, this raises the possibility that dysregulated mitochondrial lipid metabolism may facilitate chemoresistance.
Probable presence of an ubiquitous cryptic mitochondrial gene on the antisense strand of the cytochrome oxidase I gene
Eric Faure, Luis Delaye, Sandra Tribolo, Anthony Levasseur, Hervé Seligmann, Roxane-Marie Barthélémy
Biology Direct , 2011, DOI: 10.1186/1745-6150-6-56
Abstract: A positionally conserved ORF has been found on the complementary strand of the cox1 genes of both eukaryotic mitochondria (protist, plant, fungal and animal) and alpha-proteobacteria. This putative gene has been named gau for gene antisense ubiquitous in mtDNAs. The length of the deduced protein is approximately 100 amino acids. In vertebrates, several stop codons have been found in the mt gau region, and potentially functional gau regions have been found in nuclear genomes. However, a recent bioinformatics study showed that several hypothetical overlapping mt genes could be predicted, including gau; this involves the possible import of the cytosolic AGR tRNA into the mitochondria and/or the expression of mt antisense tRNAs with anticodons recognizing AGR codons according to an alternative genetic code that is induced by the presence of suppressor tRNAs. Despite an evolutionary distance of at least 1.5 to 2.0 billion years, the deduced Gau proteins share some conserved amino acid signatures and structure, which suggests a possible conserved function. Moreover, BLAST analysis identified rare, sense-oriented ESTs with poly(A) tails that include the entire gau region. Immunohistochemical analyses using an anti-Gau monoclonal antibody revealed strict co-localization of Gau proteins and a mitochondrial marker.This hypothesis could be tested by purifying the gau gene product and determining its sequence. Cell biological experiments are needed to determine the physiological role of this protein.Studies of the gau ORF will shed light on the origin of novel genes and their functions in organelles and could also have medical implications for human diseases that are caused by mitochondrial dysfunction. Moreover, this strengthens evidence for mitochondrial genes coded according to an overlapping genetic code.Mitochondria play a central role in eukaryotic metabolism, apoptosis, disease and aging [1]. Oxidative phosphorylation, which is essential for the production of ATP and for
The Creatine Kinase/Creatine Connection to Alzheimer's Disease: CK Inactivation, APP-CK Complexes and Focal Creatine Deposits
Tanja S. Bürklen,Uwe Schlattner,Ramin Homayouni,Kathleen Gough,Margaret Rak,Adriana Szeghalmi,Theo Wallimann
Journal of Biomedicine and Biotechnology , 2006, DOI: 10.1155/jbb/2006/35936
Abstract: Cytosolic brain-type creatine kinase (BB-CK), which is coexpressed with ubiquitous mitochondrial uMtCK, is significantly inactivated by oxidation, in Alzheimer's disease (AD) patients. Since CK has been shown to play a fundamental role in cellular energetics of the brain, any disturbance of this enzyme may exasperate the AD disease process. Mutations in amyloid precursor protein (APP) are associated with early onset AD and result in abnormal processing of APP, and accumulation of Aβ peptide, the main constituent of amyloid plaques in AD brain. Recent data on a direct interaction between APP and the precursor of uMtCK support an emerging relationship between AD, cellular energy levels and mitochondrial function. In addition, recently discovered creatine (Cr) deposits in the brain of transgenic AD mice, as well as in the hippocampus from AD patients, indicate a direct link between perturbed energy state, Cr metabolism and AD. Here, we review the roles of Cr and Cr-related enzymes and consider the potential value of supplementation with Cr, a potent neuroprotective substance. As a hypothesis, we consider whether Cr, if given at an early time point of the disease, may prevent or delay the course of AD-related neurodegeneration.
The Creatine Kinase/Creatine Connection to Alzheimer's Disease: CK-Inactivation, APP-CK Complexes and Focal Creatine Deposits  [cached]
Tanja S. Bürklen,Uwe Schlattner,Ramin Homayouni,Kathleen Gough
Journal of Biomedicine and Biotechnology , 2006,
Abstract: Cytosolic brain-type creatine kinase (BB-CK), which is coexpressed with ubiquitous mitochondrial uMtCK, is significantly inactivated by oxidation, in Alzheimer's disease (AD) patients. Since CK has been shown to play a fundamental role in cellular energetics of the brain, any disturbance of this enzyme may exasperate the AD disease process. Mutations in amyloid precursor protein (APP) are associated with early onset AD and result in abnormal processing of APP, and accumulation of A β peptide, the main constituent of amyloid plaques in AD brain. Recent data on a direct interaction between APP and the precursor of uMtCK support an emerging relationship between AD, cellular energy levels and mitochondrial function. In addition, recently discovered creatine (Cr) deposits in the brain of transgenic AD mice, as well as in the hippocampus from AD patients, indicate a direct link between perturbed energy state, Cr metabolism and AD. Here, we review the roles of Cr and Cr-related enzymes and consider the potential value of supplementation with Cr, a potent neuroprotective substance. As a hypothesis, we consider whether Cr, if given at an early time point of the disease, may prevent or delay the course of AD-related neurodegeneration.
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