The Experts below are selected from a list of 2121 Experts worldwide ranked by ideXlab platform
Chrisostomos Prodromou - One of the best experts on this subject based on the ideXlab platform.
-
The structure of FKBP38 in complex with the MEEVD tetratricopeptide binding-motif of Hsp90.
PloS one, 2017Co-Authors: Katie L.i.m. Blundell, S. Mark Roe, Laurence H. Pearl, M. Pal, Chrisostomos ProdromouAbstract:Tetratricopeptide (TPR) Domains are known protein interaction Domains. We show that the TPR Domain of FKBP8 selectively binds Hsp90, and interactions upstream of the conserved MEEVD motif are critical for tight binding. In contrast FKBP8 failed to bind intact Hsp70. The PPIase Domain was not essential for the interaction with Hsp90 and binding was completely encompassed by the TPR Domain alone. The conformation adopted by Hsp90 peptides, containing the conserved MEEVD motif, in the crystal structure were similar to that seen for the TPR Domains of CHIP, AIP and Tah1. The carboxylate clamp interactions with bound Hsp90 peptide were a critical component of the interaction and mutation of Lys 307, involved in the carboxylate clamp, completely disrupted the interaction with Hsp90. FKBP8 binding to Hsp90 did not substantially influence its ATPase activity.
-
Tah1 helix-swap dimerization prevents mixed Hsp90 co-chaperone complexes.
Acta Crystallographica Section D Biological Crystallography, 2015Co-Authors: Rhodri M L Morgan, Laurence H. Pearl, M. Pal, S.m. Roe, Chrisostomos ProdromouAbstract:Specific co-chaperone adaptors facilitate the recruitment of client proteins to the Hsp90 system. Tah1 binds the C-terminal conserved MEEVD motif of Hsp90, thus linking an eclectic set of client proteins to the R2TP complex for their assembly and regulation by Hsp90. Rather than the normal complement of seven α-helices seen in other tetratricopeptide repeat (TPR) Domains, Tah1 unusually consists of the first five only. Consequently, the methionine of the MEEVD peptide remains exposed to solvent when bound by Tah1. In solution Tah1 appears to be predominantly monomeric, and recent structures have failed to explain how Tah1 appears to prevent the formation of mixed TPR Domain-containing complexes such as Cpr6–(Hsp90)2–Tah1. To understand this further, the crystal structure of Tah1 in complex with the MEEVD peptide of Hsp90 was determined, which shows a helix swap involving the fifth α-helix between two adjacently bound Tah1 molecules. Dimerization of Tah1 restores the normal binding environment of the bound Hsp90 methionine residue by reconstituting a TPR binding site similar to that in seven-helix-containing TPR Domain proteins. Dimerization also explains how other monomeric TPR-Domain proteins are excluded from forming inappropriate mixed co-chaperone complexes.
-
Structural basis for the interaction of HSP90 with R2TP and TTT complexes
Acta Crystallographica Section A, 2014Co-Authors: Marc Morgan, Laurence H. Pearl, Sarah E.l. Phelps, Sarah Parry-morris, Jessica A. Downs, Sigrun Polier, Chrisostomos ProdromouAbstract:Assembly and regulation of snoRNPs, RNA polymerases, PI3-kinase-like kinases and the chromatin remodelling complexes, depends on both the TTT complex (Tel2-Tti1-Tti2) and the R2TP complex (Rvb1-Rvb2-Tah1-Pih1p in yeast and RuvBL1-RuvBL2-RPAP3-Pih1D1 in metazoa), which provide the direct connection to Hsp90. Previous studies have shown that the R2TP complex recruits client proteins to Hsp90 for their folding and assembly. In this study, we have determined the crystal structures of three complexes: Hsp90-Tah1-Pih1p, Hsp90-Tah1, Hsp90-RPAP3 (TPR1 and TPR2 Domains of RPAP3, each in complex with Hsp90). Tah1 was shown to have an unusual TPR Domain, composed of only five α-helices instead of the more usual six or seven. As expected, Tah1 TPR Domain binds to the conserved MEEVD motif at the C-terminus of HSP90. In contrast, the C-terminal region of Tah1 is unstructured in the apo form but wraps around the CS Domain of Pih1p, thus becoming ordered in the complex, and bridging the interaction between Hsp90 and Pih1p. We show a different modus operandii of Tah1-Hsp90 binding in yeast relative to RPAP3-Hsp90 interactions in metazoa. Finally, we present the crystal structure of the Pih Domain of Pih1D1 bound to a phosphopeptide of Tel2 that reveals a novel phosphopeptide-binding Domain specific for a subset of CK2 phosphorylation sites. Together these structures define the basis by which the R2TP complex connects the Hsp90 chaperone system to the TTT complex.
-
structure of the TPR Domain of aip lack of client protein interaction with the c terminal α 7 helix of the TPR Domain of aip is sufficient for pituitary adenoma predisposition
PLOS ONE, 2012Co-Authors: Rhodri M L Morgan, Laura C Hernandezramirez, Giampaolo Trivellin, Lihong Zhou, Marta Korbonits, Chrisostomos ProdromouAbstract:Mutations of the aryl hydrocarbon receptor interacting protein (AIP) have been associated with familial isolated pituitary adenomas predisposing to young-onset acromegaly and gigantism. The precise tumorigenic mechanism is not well understood as AIP interacts with a large number of independent proteins as well as three chaperone systems, HSP90, HSP70 and TOMM20. We have determined the structure of the TPR Domain of AIP at high resolution, which has allowed a detailed analysis of how disease-associated mutations impact on the structural integrity of the TPR Domain. A subset of C-terminal α-7 helix (Cα-7h) mutations, R304* (nonsense mutation), R304Q, Q307* and R325Q, a known site for AhR and PDE4A5 client-protein interaction, occur beyond those that interact with the conserved MEEVD and EDDVE sequences of HSP90 and TOMM20. These C-terminal AIP mutations appear to only disrupt client-protein binding to the Cα-7h, while chaperone binding remains unaffected, suggesting that failure of client-protein interaction with the Cα-7h is sufficient to predispose to pituitary adenoma. We have also identified a molecular switch in the AIP TPR-Domain that allows recognition of both the conserved HSP90 motif, MEEVD, and the equivalent sequence (EDDVE) of TOMM20.
-
Chaperone ligand-discrimination by the TPR-Domain Protein Tah1
Biochemical Journal, 2008Co-Authors: Stefan H Millson, Cara K. Vaughan, Chao Zhai, Maruf M. U. Ali, Barry Panaretou, Peter W. Piper, Laurence H. Pearl, Chrisostomos ProdromouAbstract:Tah1 has been identified as a tetratricopeptide (TPR)-Domain protein. TPR-Domain proteins are involved in protein-protein interactions and a number have been characterized that interact either with Hsp70 or Hsp90, but a few can bind both chaperones. Independent studies suggest that Tah1 interacts with Hsp90, but whether it can also interact with Hsp70/Ssa1 has not been investigated. Amino acid sequence alignments suggest that Tah1 is most similar to the TPR2b-Domain of Hop which when mutated reduces binding to both Hsp90 and Hsp70. Our alignments suggest that there are three TPR-Domain motifs in Tah1 which is consistent with the architecture of the TPR2b-Domain. We find that Tah1 is specific for Hsp90, able to bind tightly the yeast Hsp90, and the human Hsp90α and Hsp90β proteins, but not the yeast Hsp70, Ssa1 isoform. Tah1 acheives ligand discrimination by favourably binding the methionine residue in the conserved MEEVD-motif (Hsp90) and positively discriminating against the first valine residue in the VEEVD-motif (Ssa1). We also show that Tah1 can affect the ATPase activity of Hsp90, in common with some other TPR-Domain proteins.
Mario D. Galigniana - One of the best experts on this subject based on the ideXlab platform.
-
The Emerging Role of TPR-Domain Immunophilins in the Mechanism of Action of Steroid Receptors
Nuclear Receptor Research, 2014Co-Authors: Gisela I. Mazaira, Mariana Lagadari, Alejandra G. Erlejman, Mario D. GalignianaAbstract:In the absence of ligand, some members of nuclear receptor family such as corticosteroid receptors are primarily located in the cytoplasm, and they rapidly accumulate in the nucleus upon ligand-binding. Other members of the family such as the estrogen receptor are mostly nuclear. Regardless of their primary location, these oligomeric proteins undergo a dynamic nuclear-cytoplasmic shuttling, and their transport through the cytoplasmic compartment has always been assumed to occur in a stochastic manner by simple diffusion. Although heuristic, this oversimplified model has never been demonstrated. Moreover, it has always been assumed that the first step related to receptor activation is the dissociation of the Hsp90-based heterocomplex, a process referred to as `transformation.' Nonetheless, recent experimental evidence indicates that the chaperone machinery is required for the retrotransport of the receptor throughout the cytoplasm and facilitates its active passage through the nuclear pore. Therefore, transformation is actually a nuclear event. A group of Hsp90-binding cochaperones belonging to the immunophilin family plays a cardinal role not only in the mechanism for receptor movement, but also in nuclear events leading to interactions with nuclear sites of action and the regulation of transcriptional activity. In this article we analyze the importance of molecular chaperones and TPR-Domain immunophilins in the molecular mechanism of action of steroid receptors.
-
Molecular Chaperone Activity and Biological Regulatory Actions of the TPR-Domain Immunophilins FKBP51 and FKBP52
Current protein & peptide science, 2014Co-Authors: Alejandra G. Erlejman, Mariana Lagadari, Diondra C. Harris, Marc B. Cox, Mario D. GalignianaAbstract:Immunophilins comprise a family of intracellular proteins with peptidyl-prolyl-(cis/trans)-isomerase activity. These foldases are abundant, ubiquitous, and able to bind immunosuppressant drugs, from which the term immunophilin derives. Family members are found in abundance in virtually all organisms and subcellular compartments, and their amino acid sequences are conserved phylogenetically. Immunophilins possess the ability to function as molecular chaperones favoring the proper folding and biological regulation of their biological actions. Their ability to interact via their TPR Domains with the 90-kDa heat-shock protein, and through this chaperone, with several signalling cascade factors is of particular importance. Among the family members, the highly homologous proteins FKBP51 and FKBP52 were first characterized due to their ability to interact with steroid hormone receptors. Since then, much progress has been made in understanding the mechanisms by which they regulate receptor signaling and the resulting roles they play not only in endocrine processes, but also in cell architecture, neurodifferentiation, and tumor progression. In this article we review the most relevant features of these two immunophilins and their potential as pharmacologic targets.
-
The 90-kDa heat-shock protein (Hsp90)-binding immunophilin FKBP51 is a mitochondrial protein that translocates to the nucleus to protect cells against oxidative stress.
The Journal of biological chemistry, 2011Co-Authors: Luciana I. Gallo, Mariana Lagadari, Graciela Piwien-pilipuk, Mario D. GalignianaAbstract:Confocal microscopy images revealed that the tetratricopeptide repeat motif (TPR) Domain immunophilin FKBP51 shows colocalization with the specific mitochondrial marker MitoTracker. Signal specificity was tested with different antibodies and by FKBP51 knockdown. This unexpected subcellular localization of FKBP51 was confirmed by colocalization studies with other mitochondrial proteins, biochemical fractionation, and electron microscopy imaging. Interestingly, FKBP51 forms complexes in mitochondria with the glucocorticoid receptor and the Hsp90/Hsp70-based chaperone heterocomplex. Although Hsp90 inhibitors favor FKBP51 translocation from mitochondria to the nucleus in a reversible manner, TPR Domain-deficient mutants of FKBP51 are constitutively nuclear and fully excluded from mitochondria, suggesting that a functional TPR Domain is required for its mitochondrial localization. FKBP51 overexpression protects cells against oxidative stress, whereas FKBP51 knockdown makes them more sensitive to injury. In summary, this is the first demonstration that FKBP51 is a major mitochondrial factor that undergoes nuclear-mitochondrial shuttling, an observation that may be related to antiapoptotic mechanisms triggered during the stress response.
-
TPR Domain immunophilin fkbp51 is a major mitochondrial protein that protects cells against oxidative stress
Journal of Biological Chemistry, 2011Co-Authors: Luciana I. Gallo, Mariana Lagadari, Graciela Piwien Pilipuk, Mario D. GalignianaAbstract:Fil: Gallo, Luciana Ines. Consejo Nacional de Investigaciones Cientificas y Tecnicas. Instituto de Biologia y Medicina Experimental (i); Argentina
-
Role of molecular chaperones and TPR-Domain proteins in the cytoplasmic transport of steroid receptors and their passage through the nuclear pore
Nucleus (Austin Tex.), 2010Co-Authors: Mario D. Galigniana, Alejandra G. Erlejman, Pablo Christian Echeverria, Graciela Piwien-pilipukAbstract:In the absence of hormone, corticosteroid receptors such as GR (glucocorticoid receptor) and MR (mineralocorticoid receptor) are primarily located in the cytoplasm. Upon steroid-binding, they rapidly accumulate in the nucleus. Regardless of their primary location, these receptors and many other nuclear factors undergo a constant and dynamic nucleocytoplasmic shuttling. All members of the steroid receptor family are known to form large oligomeric structures with the heat-shock proteins of 90-kDa (hsp90) and 70-kDa (hsp70), the small acidic protein p23, and a tetratricopeptide repeat (TPR)-Domain protein such as FK506-binding proteins (FKBPs), cyclophilins (CyPs) or the serine/threonine protein phosphatase 5 (PP5). It has always been stated that the dissociation of the chaperone heterocomplex (a process normally referred to as receptor “transformation”) is the first step that permits the nuclear import of steroid receptors. However the experimental evidence is consistent with a model where the chaperone mac...
Laurence H. Pearl - One of the best experts on this subject based on the ideXlab platform.
-
The structure of FKBP38 in complex with the MEEVD tetratricopeptide binding-motif of Hsp90.
PloS one, 2017Co-Authors: Katie L.i.m. Blundell, S. Mark Roe, Laurence H. Pearl, M. Pal, Chrisostomos ProdromouAbstract:Tetratricopeptide (TPR) Domains are known protein interaction Domains. We show that the TPR Domain of FKBP8 selectively binds Hsp90, and interactions upstream of the conserved MEEVD motif are critical for tight binding. In contrast FKBP8 failed to bind intact Hsp70. The PPIase Domain was not essential for the interaction with Hsp90 and binding was completely encompassed by the TPR Domain alone. The conformation adopted by Hsp90 peptides, containing the conserved MEEVD motif, in the crystal structure were similar to that seen for the TPR Domains of CHIP, AIP and Tah1. The carboxylate clamp interactions with bound Hsp90 peptide were a critical component of the interaction and mutation of Lys 307, involved in the carboxylate clamp, completely disrupted the interaction with Hsp90. FKBP8 binding to Hsp90 did not substantially influence its ATPase activity.
-
Tah1 helix-swap dimerization prevents mixed Hsp90 co-chaperone complexes.
Acta Crystallographica Section D Biological Crystallography, 2015Co-Authors: Rhodri M L Morgan, Laurence H. Pearl, M. Pal, S.m. Roe, Chrisostomos ProdromouAbstract:Specific co-chaperone adaptors facilitate the recruitment of client proteins to the Hsp90 system. Tah1 binds the C-terminal conserved MEEVD motif of Hsp90, thus linking an eclectic set of client proteins to the R2TP complex for their assembly and regulation by Hsp90. Rather than the normal complement of seven α-helices seen in other tetratricopeptide repeat (TPR) Domains, Tah1 unusually consists of the first five only. Consequently, the methionine of the MEEVD peptide remains exposed to solvent when bound by Tah1. In solution Tah1 appears to be predominantly monomeric, and recent structures have failed to explain how Tah1 appears to prevent the formation of mixed TPR Domain-containing complexes such as Cpr6–(Hsp90)2–Tah1. To understand this further, the crystal structure of Tah1 in complex with the MEEVD peptide of Hsp90 was determined, which shows a helix swap involving the fifth α-helix between two adjacently bound Tah1 molecules. Dimerization of Tah1 restores the normal binding environment of the bound Hsp90 methionine residue by reconstituting a TPR binding site similar to that in seven-helix-containing TPR Domain proteins. Dimerization also explains how other monomeric TPR-Domain proteins are excluded from forming inappropriate mixed co-chaperone complexes.
-
Structural basis for the interaction of HSP90 with R2TP and TTT complexes
Acta Crystallographica Section A, 2014Co-Authors: Marc Morgan, Laurence H. Pearl, Sarah E.l. Phelps, Sarah Parry-morris, Jessica A. Downs, Sigrun Polier, Chrisostomos ProdromouAbstract:Assembly and regulation of snoRNPs, RNA polymerases, PI3-kinase-like kinases and the chromatin remodelling complexes, depends on both the TTT complex (Tel2-Tti1-Tti2) and the R2TP complex (Rvb1-Rvb2-Tah1-Pih1p in yeast and RuvBL1-RuvBL2-RPAP3-Pih1D1 in metazoa), which provide the direct connection to Hsp90. Previous studies have shown that the R2TP complex recruits client proteins to Hsp90 for their folding and assembly. In this study, we have determined the crystal structures of three complexes: Hsp90-Tah1-Pih1p, Hsp90-Tah1, Hsp90-RPAP3 (TPR1 and TPR2 Domains of RPAP3, each in complex with Hsp90). Tah1 was shown to have an unusual TPR Domain, composed of only five α-helices instead of the more usual six or seven. As expected, Tah1 TPR Domain binds to the conserved MEEVD motif at the C-terminus of HSP90. In contrast, the C-terminal region of Tah1 is unstructured in the apo form but wraps around the CS Domain of Pih1p, thus becoming ordered in the complex, and bridging the interaction between Hsp90 and Pih1p. We show a different modus operandii of Tah1-Hsp90 binding in yeast relative to RPAP3-Hsp90 interactions in metazoa. Finally, we present the crystal structure of the Pih Domain of Pih1D1 bound to a phosphopeptide of Tel2 that reveals a novel phosphopeptide-binding Domain specific for a subset of CK2 phosphorylation sites. Together these structures define the basis by which the R2TP complex connects the Hsp90 chaperone system to the TTT complex.
-
Chaperone ligand-discrimination by the TPR-Domain Protein Tah1
Biochemical Journal, 2008Co-Authors: Stefan H Millson, Cara K. Vaughan, Chao Zhai, Maruf M. U. Ali, Barry Panaretou, Peter W. Piper, Laurence H. Pearl, Chrisostomos ProdromouAbstract:Tah1 has been identified as a tetratricopeptide (TPR)-Domain protein. TPR-Domain proteins are involved in protein-protein interactions and a number have been characterized that interact either with Hsp70 or Hsp90, but a few can bind both chaperones. Independent studies suggest that Tah1 interacts with Hsp90, but whether it can also interact with Hsp70/Ssa1 has not been investigated. Amino acid sequence alignments suggest that Tah1 is most similar to the TPR2b-Domain of Hop which when mutated reduces binding to both Hsp90 and Hsp70. Our alignments suggest that there are three TPR-Domain motifs in Tah1 which is consistent with the architecture of the TPR2b-Domain. We find that Tah1 is specific for Hsp90, able to bind tightly the yeast Hsp90, and the human Hsp90α and Hsp90β proteins, but not the yeast Hsp70, Ssa1 isoform. Tah1 acheives ligand discrimination by favourably binding the methionine residue in the conserved MEEVD-motif (Hsp90) and positively discriminating against the first valine residue in the VEEVD-motif (Ssa1). We also show that Tah1 can affect the ATPase activity of Hsp90, in common with some other TPR-Domain proteins.
-
Chaperone ligand-discrimination by the TPR-Domain protein Tah1
The Biochemical journal, 2008Co-Authors: Stefan H Millson, Cara K. Vaughan, Chao Zhai, Maruf M. U. Ali, Barry Panaretou, Peter W. Piper, Laurence H. Pearl, Chrisostomos ProdromouAbstract:Tah1 [TPR (tetratricopeptide repeat)-containing protein associated with Hsp (heat-shock protein) 90] has been identified as a TPR-Domain protein. TPR-Domain proteins are involved in protein–protein interactions and a number have been characterized that interact either with Hsp70 or Hsp90, but a few can bind both chaperones. Independent studies suggest that Tah1 interacts with Hsp90, but whether it can also interact with Hsp70/Ssa1 has not been investigated. Amino-acid-sequence alignments suggest that Tah1 is most similar to the TPR2b Domain of Hop (Hsp-organizing protein) which when mutated reduces binding to both Hsp90 and Hsp70. Our alignments suggest that there are three TPR-Domain motifs in Tah1, which is consistent with the architecture of the TPR2b Domain. In the present study we find that Tah1 is specific for Hsp90, and is able to bind tightly the yeast Hsp90, and the human Hsp90α and Hsp90β proteins, but not the yeast Hsp70 Ssa1 isoform. Tah1 acheives ligand discrimination by favourably binding the methionine residue in the conserved MEEVD motif (Hsp90) and positively discriminating against the first valine residue in the VEEVD motif (Ssa1). In the present study we also show that Tah1 can affect the ATPase activity of Hsp90, in common with some other TPR-Domain proteins.
Greg Lemke - One of the best experts on this subject based on the ideXlab platform.
-
mutations in a gene encoding a novel sh3 TPR Domain protein cause autosomal recessive charcot marie tooth type 4c neuropathy
American Journal of Human Genetics, 2003Co-Authors: Jan Senderek, Carsten Bergmann, Claudia Stendel, Jutta Kirfel, Nathalie Verpoorten, Peter De Jonghe, Vincent Timmerman, Roman Chrast, Mark H G Verheijen, Greg LemkeAbstract:Charcot-Marie-Tooth disease type 4C (CMT4C) is a childhood-onset demyelinating form of hereditary motor and sensory neuropathy associated with an early-onset scoliosis and a distinct Schwann cell pathology. CMT4C is inherited as an autosomal recessive trait and has been mapped to a 13-cM linkage interval on chromosome 5q23-q33. By homozygosity mapping and allele-sharing analysis, we refined the CMT4C locus to a suggestive critical region of 1.7 Mb. We subsequently identified mutations in an uncharacterized transcript, KIAA1985, in 12 families with autosomal recessive neuropathy. We observed eight distinct protein-truncating mutations and three nonconservative missense mutations affecting amino acids conserved through evolution. In all families, we identified a mutation on each disease allele, either in the homozygous or in the compound heterozygous state. The CMT4C gene is strongly expressed in neural tissues, including peripheral nerve tissue. The translated protein defines a new protein family of unknown function with putative orthologues in vertebrates. Comparative sequence alignments indicate that members of this protein family contain multiple SH3 and TPR Domains that are likely involved in the formation of protein complexes.
-
Mutations in a Gene Encoding a Novel SH3/TPR Domain Protein Cause Autosomal Recessive Charcot-Marie-Tooth Type 4C Neuropathy
American journal of human genetics, 2003Co-Authors: Jan Senderek, Carsten Bergmann, Claudia Stendel, Jutta Kirfel, Nathalie Verpoorten, Peter De Jonghe, Vincent Timmerman, Roman Chrast, Mark H G Verheijen, Greg LemkeAbstract:Charcot-Marie-Tooth disease type 4C (CMT4C) is a childhood-onset demyelinating form of hereditary motor and sensory neuropathy associated with an early-onset scoliosis and a distinct Schwann cell pathology. CMT4C is inherited as an autosomal recessive trait and has been mapped to a 13-cM linkage interval on chromosome 5q23-q33. By homozygosity mapping and allele-sharing analysis, we refined the CMT4C locus to a suggestive critical region of 1.7 Mb. We subsequently identified mutations in an uncharacterized transcript, KIAA1985, in 12 families with autosomal recessive neuropathy. We observed eight distinct protein-truncating mutations and three nonconservative missense mutations affecting amino acids conserved through evolution. In all families, we identified a mutation on each disease allele, either in the homozygous or in the compound heterozygous state. The CMT4C gene is strongly expressed in neural tissues, including peripheral nerve tissue. The translated protein defines a new protein family of unknown function with putative orthologues in vertebrates. Comparative sequence alignments indicate that members of this protein family contain multiple SH3 and TPR Domains that are likely involved in the formation of protein complexes.
Cord Dohrmann - One of the best experts on this subject based on the ideXlab platform.
-
control of triglyceride storage by a wd40 TPR Domain protein
EMBO Reports, 2003Co-Authors: Thomas Häder, Sandra Müller, Miguel Aguilera, Karsten Eulenberg, Arnd Steuernagel, Thomas Ciossek, Ronald P. Kühnlein, Lydia Lemaire, Rüdiger Fritsch, Cord DohrmannAbstract:Obesity is a metabolic disorder related to improper control of energy uptake and expenditure, which results in excessive accumulation of body fat. Initial insights into the genetic pathways that regulate energy metabolism have been provided by a discrete number of obesity-related genes that have been identified in mammals. Here, we report the identification of the adipose (adp) gene, the mutation of which causes obesity in Drosophila. Loss of adp activity promotes increased fat storage, which extends the lifespan of mutant flies under starvation conditions. By contrast, adp gain-of-function causes a specific reduction of the fat body in Drosophila. adp encodes an evolutionarily conserved WD40/tetratricopeptide-repeat-Domain protein that is likely to represent an intermediate in a novel signalling pathway.
-
Control of triglyceride storage by a WD40/TPR-Domain protein
EMBO reports, 2003Co-Authors: Thomas Häder, Sandra Müller, Miguel Aguilera, Karsten Eulenberg, Arnd Steuernagel, Thomas Ciossek, Ronald P. Kühnlein, Lydia Lemaire, Rüdiger Fritsch, Cord DohrmannAbstract:Obesity is a metabolic disorder related to improper control of energy uptake and expenditure, which results in excessive accumulation of body fat. Initial insights into the genetic pathways that regulate energy metabolism have been provided by a discrete number of obesity-related genes that have been identified in mammals. Here, we report the identification of the adipose (adp) gene, the mutation of which causes obesity in Drosophila. Loss of adp activity promotes increased fat storage, which extends the lifespan of mutant flies under starvation conditions. By contrast, adp gain-of-function causes a specific reduction of the fat body in Drosophila. adp encodes an evolutionarily conserved WD40/tetratricopeptide-repeat-Domain protein that is likely to represent an intermediate in a novel signalling pathway.
