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Antonio Raggi - One of the best experts on this subject based on the ideXlab platform.
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the role of histidine proline rich glycoprotein as zinc chaperone for skeletal muscle amp deaminase
Biomolecules, 2014Co-Authors: Maria Ranieriraggi, Arthur J G Moir, Antonio RaggiAbstract:Metallochaperones function as intracellular shuttles for metal ions. At present, no evidence for the existence of any eukaryotic zinc-chaperone has been provided although metallochaperones could be critical for the physiological functions of Zn2+ metalloenzymes. We propose that the complex formed in skeletal muscle by the Zn2+ metalloenzyme AMP deaminase (AMPD) and the metal binding protein histidine-proline-rich glycoprotein (HPRG) acts in this manner. HPRG is a major plasma protein. Recent investigations have reported that skeletal muscle cells do not synthesize HPRG but instead actively internalize plasma HPRG. X-ray absorption spectroscopy (XAS) performed on fresh preparations of rabbit skeletal muscle AMPD provided evidence for a dinuclear zinc site in the enzyme compatible with a (μ-aqua)(μ-carboxylato)dizinc(II) core with two histidine residues at each metal site. XAS on HPRG isolated from the AMPD complex showed that zinc is bound to the protein in a dinuclear cluster where each Zn2+ ion is coordinated by three histidine and one heavier ligand, likely sulfur from cysteine. We describe the existence in mammalian HPRG of a specific zinc binding site distinct from the His-Pro-rich region. The participation of HPRG in the assembly and maintenance of skeletal muscle AMPD by acting as a zinc chaperone is also demonstrated.
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characterization of the zinc binding site of the histidine proline rich glycoprotein associated with rabbit skeletal muscle amp deaminase
Journal of Biological Chemistry, 2003Co-Authors: Stefano Mangani, Maria Ranieriraggi, Arthur J G Moir, Daniela Martini, Wolfram Meyerklaucke, Antonio RaggiAbstract:The AMP deaminase-associated variant of histidine-proline-rich glycoprotein (HPRG) is isolated from rabbit skeletal muscle by a modification of the protocol previously used for the purification of AMP deaminase. This procedure yields highly pure HPRG suitable for investigation by x-ray absorption spectroscopy of the zinc-binding behavior of the protein. X-ray absorption spectroscopy analysis of a 2:1 zinc-HPRG complex shows that zinc is bound to the protein, most probably in a dinuclear cluster where each Zn2+ ion is coordinated, on average, by three histidine ligands and one heavier ligand, likely a sulfur from a cysteine. 11 cysteines of HPRG from different species are totally conserved, suggesting that five disulfide bridges are essential for the proper folding of the protein. At least another cysteine is present at different positions in the histidine-proline-rich domain of HPRG in all species, suggesting that this cysteine is the candidate for zinc ligation in the muscle variant of HPRG. The same conclusion is likely to be true for the six histidines used by the protein as zinc ligands. The presence in muscle HPRG of a specific zinc-binding site permits us to envisage the addition of HPRG into the family of metallochaperones. In this view, HPRG may enhance the in vivo stability of metalloenzymes such as AMP deaminase.
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presence in human skeletal muscle of an amp deaminase associated protein that reacts with an antibody to human plasma histidine proline rich glycoprotein
Journal of Histochemistry and Cytochemistry, 1999Co-Authors: A Sabbatini, Maria Ranieriraggi, Arthur J G Moir, L Pollina, P Viacava, John R Ashby, Antonio RaggiAbstract:Histidine-proline-rich glycoprotein (HPRG) is a protein that is synthesized by parenchimal liver cells. The protein has been implicated in a number of plasma-specific processes, including blood coagulation and fibrinolysis. We have recently reported the association of an HPRG-like protein with rabbit skeletal muscle AMP deaminase (AMPD). The results of the immunological analysis reported here demonstrate that an antibody against human plasma HPRG reacts with an AMPD preparation from human skeletal muscle. To probe the localization of the putative HPRG-like protein in human skeletal muscle, serial sections from frozen biopsy specimens were processed for immunohistochemical and histoenzymatic stains. A selective binding of the anti-HPRG antibody to Type IIB muscle fibers was detected, suggesting a preferential association of the novel protein to the AMPD isoenzyme contained in the fast-twitch glycolytic fibers.
Maria Ranieriraggi - One of the best experts on this subject based on the ideXlab platform.
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the role of histidine proline rich glycoprotein as zinc chaperone for skeletal muscle amp deaminase
Biomolecules, 2014Co-Authors: Maria Ranieriraggi, Arthur J G Moir, Antonio RaggiAbstract:Metallochaperones function as intracellular shuttles for metal ions. At present, no evidence for the existence of any eukaryotic zinc-chaperone has been provided although metallochaperones could be critical for the physiological functions of Zn2+ metalloenzymes. We propose that the complex formed in skeletal muscle by the Zn2+ metalloenzyme AMP deaminase (AMPD) and the metal binding protein histidine-proline-rich glycoprotein (HPRG) acts in this manner. HPRG is a major plasma protein. Recent investigations have reported that skeletal muscle cells do not synthesize HPRG but instead actively internalize plasma HPRG. X-ray absorption spectroscopy (XAS) performed on fresh preparations of rabbit skeletal muscle AMPD provided evidence for a dinuclear zinc site in the enzyme compatible with a (μ-aqua)(μ-carboxylato)dizinc(II) core with two histidine residues at each metal site. XAS on HPRG isolated from the AMPD complex showed that zinc is bound to the protein in a dinuclear cluster where each Zn2+ ion is coordinated by three histidine and one heavier ligand, likely sulfur from cysteine. We describe the existence in mammalian HPRG of a specific zinc binding site distinct from the His-Pro-rich region. The participation of HPRG in the assembly and maintenance of skeletal muscle AMPD by acting as a zinc chaperone is also demonstrated.
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immunohistochemical analysis of human skeletal muscle amp deaminase deficiency evidence of a correlation between the muscle hprg content and the level of the residual amp deaminase activity
Journal of Muscle Research and Cell Motility, 2006Co-Authors: A Sabbatini, Maria Ranieriraggi, Arthur J G Moir, Daniela Martini, Antonio Toscano, M Aguennouz, Enza Polizzi, Alba Migliorato, Olimpia Musumeci, Giuseppe VitaAbstract:We have previously described that, in healthy human skeletal muscle, an anti-histidine-proline-rich-glycoprotein (HPRG) antibody selectively binds to type IIB fibers that are well known to contain the highest level of AMP deaminase (AMPD) activity, suggesting an association of the HPRG-like protein to the enzyme isoform M. The present paper reports an immunohistochemical study performed on human skeletal muscle biopsies from patients with AMPD deficiency and carried out utilizing both the anti-HPRG antibody and an anti-AMPD antibody specific for the isoform M. A correlation between the muscle content of the HPRG-like protein and the level of AMPD activity was demonstrated. In the specimens from patients with Acquired AMPD deficiency the HPRG-immunoreactivity was less intense than that shown by the control subjects and was related to the residual AMPD activity. The patients affected by Primary and Coincidental AMPD deficiency, which were characterized by an absence of enzyme activity and AMPD immunoreactivity, showed the lowest HPRG immunoreactivity that was clearly detectable by Western blot analysis, but not by immunohistochemistry. The interpretation of the significance of these observations suggests a physiological mutual dependence between skeletal muscle HPRG and AMPD polypeptides with regard to their stability.
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characterization of the zinc binding site of the histidine proline rich glycoprotein associated with rabbit skeletal muscle amp deaminase
Journal of Biological Chemistry, 2003Co-Authors: Stefano Mangani, Maria Ranieriraggi, Arthur J G Moir, Daniela Martini, Wolfram Meyerklaucke, Antonio RaggiAbstract:The AMP deaminase-associated variant of histidine-proline-rich glycoprotein (HPRG) is isolated from rabbit skeletal muscle by a modification of the protocol previously used for the purification of AMP deaminase. This procedure yields highly pure HPRG suitable for investigation by x-ray absorption spectroscopy of the zinc-binding behavior of the protein. X-ray absorption spectroscopy analysis of a 2:1 zinc-HPRG complex shows that zinc is bound to the protein, most probably in a dinuclear cluster where each Zn2+ ion is coordinated, on average, by three histidine ligands and one heavier ligand, likely a sulfur from a cysteine. 11 cysteines of HPRG from different species are totally conserved, suggesting that five disulfide bridges are essential for the proper folding of the protein. At least another cysteine is present at different positions in the histidine-proline-rich domain of HPRG in all species, suggesting that this cysteine is the candidate for zinc ligation in the muscle variant of HPRG. The same conclusion is likely to be true for the six histidines used by the protein as zinc ligands. The presence in muscle HPRG of a specific zinc-binding site permits us to envisage the addition of HPRG into the family of metallochaperones. In this view, HPRG may enhance the in vivo stability of metalloenzymes such as AMP deaminase.
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presence in human skeletal muscle of an amp deaminase associated protein that reacts with an antibody to human plasma histidine proline rich glycoprotein
Journal of Histochemistry and Cytochemistry, 1999Co-Authors: A Sabbatini, Maria Ranieriraggi, Arthur J G Moir, L Pollina, P Viacava, John R Ashby, Antonio RaggiAbstract:Histidine-proline-rich glycoprotein (HPRG) is a protein that is synthesized by parenchimal liver cells. The protein has been implicated in a number of plasma-specific processes, including blood coagulation and fibrinolysis. We have recently reported the association of an HPRG-like protein with rabbit skeletal muscle AMP deaminase (AMPD). The results of the immunological analysis reported here demonstrate that an antibody against human plasma HPRG reacts with an AMPD preparation from human skeletal muscle. To probe the localization of the putative HPRG-like protein in human skeletal muscle, serial sections from frozen biopsy specimens were processed for immunohistochemical and histoenzymatic stains. A selective binding of the anti-HPRG antibody to Type IIB muscle fibers was detected, suggesting a preferential association of the novel protein to the AMPD isoenzyme contained in the fast-twitch glycolytic fibers.
Arthur J G Moir - One of the best experts on this subject based on the ideXlab platform.
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the role of histidine proline rich glycoprotein as zinc chaperone for skeletal muscle amp deaminase
Biomolecules, 2014Co-Authors: Maria Ranieriraggi, Arthur J G Moir, Antonio RaggiAbstract:Metallochaperones function as intracellular shuttles for metal ions. At present, no evidence for the existence of any eukaryotic zinc-chaperone has been provided although metallochaperones could be critical for the physiological functions of Zn2+ metalloenzymes. We propose that the complex formed in skeletal muscle by the Zn2+ metalloenzyme AMP deaminase (AMPD) and the metal binding protein histidine-proline-rich glycoprotein (HPRG) acts in this manner. HPRG is a major plasma protein. Recent investigations have reported that skeletal muscle cells do not synthesize HPRG but instead actively internalize plasma HPRG. X-ray absorption spectroscopy (XAS) performed on fresh preparations of rabbit skeletal muscle AMPD provided evidence for a dinuclear zinc site in the enzyme compatible with a (μ-aqua)(μ-carboxylato)dizinc(II) core with two histidine residues at each metal site. XAS on HPRG isolated from the AMPD complex showed that zinc is bound to the protein in a dinuclear cluster where each Zn2+ ion is coordinated by three histidine and one heavier ligand, likely sulfur from cysteine. We describe the existence in mammalian HPRG of a specific zinc binding site distinct from the His-Pro-rich region. The participation of HPRG in the assembly and maintenance of skeletal muscle AMPD by acting as a zinc chaperone is also demonstrated.
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immunohistochemical analysis of human skeletal muscle amp deaminase deficiency evidence of a correlation between the muscle hprg content and the level of the residual amp deaminase activity
Journal of Muscle Research and Cell Motility, 2006Co-Authors: A Sabbatini, Maria Ranieriraggi, Arthur J G Moir, Daniela Martini, Antonio Toscano, M Aguennouz, Enza Polizzi, Alba Migliorato, Olimpia Musumeci, Giuseppe VitaAbstract:We have previously described that, in healthy human skeletal muscle, an anti-histidine-proline-rich-glycoprotein (HPRG) antibody selectively binds to type IIB fibers that are well known to contain the highest level of AMP deaminase (AMPD) activity, suggesting an association of the HPRG-like protein to the enzyme isoform M. The present paper reports an immunohistochemical study performed on human skeletal muscle biopsies from patients with AMPD deficiency and carried out utilizing both the anti-HPRG antibody and an anti-AMPD antibody specific for the isoform M. A correlation between the muscle content of the HPRG-like protein and the level of AMPD activity was demonstrated. In the specimens from patients with Acquired AMPD deficiency the HPRG-immunoreactivity was less intense than that shown by the control subjects and was related to the residual AMPD activity. The patients affected by Primary and Coincidental AMPD deficiency, which were characterized by an absence of enzyme activity and AMPD immunoreactivity, showed the lowest HPRG immunoreactivity that was clearly detectable by Western blot analysis, but not by immunohistochemistry. The interpretation of the significance of these observations suggests a physiological mutual dependence between skeletal muscle HPRG and AMPD polypeptides with regard to their stability.
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characterization of the zinc binding site of the histidine proline rich glycoprotein associated with rabbit skeletal muscle amp deaminase
Journal of Biological Chemistry, 2003Co-Authors: Stefano Mangani, Maria Ranieriraggi, Arthur J G Moir, Daniela Martini, Wolfram Meyerklaucke, Antonio RaggiAbstract:The AMP deaminase-associated variant of histidine-proline-rich glycoprotein (HPRG) is isolated from rabbit skeletal muscle by a modification of the protocol previously used for the purification of AMP deaminase. This procedure yields highly pure HPRG suitable for investigation by x-ray absorption spectroscopy of the zinc-binding behavior of the protein. X-ray absorption spectroscopy analysis of a 2:1 zinc-HPRG complex shows that zinc is bound to the protein, most probably in a dinuclear cluster where each Zn2+ ion is coordinated, on average, by three histidine ligands and one heavier ligand, likely a sulfur from a cysteine. 11 cysteines of HPRG from different species are totally conserved, suggesting that five disulfide bridges are essential for the proper folding of the protein. At least another cysteine is present at different positions in the histidine-proline-rich domain of HPRG in all species, suggesting that this cysteine is the candidate for zinc ligation in the muscle variant of HPRG. The same conclusion is likely to be true for the six histidines used by the protein as zinc ligands. The presence in muscle HPRG of a specific zinc-binding site permits us to envisage the addition of HPRG into the family of metallochaperones. In this view, HPRG may enhance the in vivo stability of metalloenzymes such as AMP deaminase.
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presence in human skeletal muscle of an amp deaminase associated protein that reacts with an antibody to human plasma histidine proline rich glycoprotein
Journal of Histochemistry and Cytochemistry, 1999Co-Authors: A Sabbatini, Maria Ranieriraggi, Arthur J G Moir, L Pollina, P Viacava, John R Ashby, Antonio RaggiAbstract:Histidine-proline-rich glycoprotein (HPRG) is a protein that is synthesized by parenchimal liver cells. The protein has been implicated in a number of plasma-specific processes, including blood coagulation and fibrinolysis. We have recently reported the association of an HPRG-like protein with rabbit skeletal muscle AMP deaminase (AMPD). The results of the immunological analysis reported here demonstrate that an antibody against human plasma HPRG reacts with an AMPD preparation from human skeletal muscle. To probe the localization of the putative HPRG-like protein in human skeletal muscle, serial sections from frozen biopsy specimens were processed for immunohistochemical and histoenzymatic stains. A selective binding of the anti-HPRG antibody to Type IIB muscle fibers was detected, suggesting a preferential association of the novel protein to the AMPD isoenzyme contained in the fast-twitch glycolytic fibers.
William A. Gahl - One of the best experts on this subject based on the ideXlab platform.
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a divalent interaction between hps1 and hps4 is required for the formation of the biogenesis of lysosome related organelle complex 3 bloc 3
Biochimica et Biophysica Acta, 2013Co-Authors: William A. Gahl, Carmelo Carmonarivera, Dimitre R Simeonov, Nicholas D Cardillo, Carmen L CadillaAbstract:Abstract Hermansky–Pudlak syndrome (HPS) is a group of rare autosomal recessive disorders characterized by oculocutaneous albinism, a bleeding tendency, and sporadic pulmonary fibrosis, granulomatous colitis or infections. Nine HPS-causing genes have been identified in humans. HPS-1 is the most severe subtype with a prevalence of ~ 1/1800 in northwest Puerto Rico due to a founder mutation in the HPS1 gene. Mutations in HPS genes affect the biogenesis of lysosome-related organelles such as melanosomes in melanocytes and platelet dense granules. Two of these genes ( HPS1 and HPS4 ) encode the HPS1 and HPS4 proteins, which assemble to form a complex known as Biogenesis of Lysosome-related Organelle Complex 3 (BLOC-3). We report the identification of the interacting regions in HPS1 and HPS4 required for the formation of this complex. Two regions in HPS1, spanning amino acids 1–249 and 506–700 are required for binding to HPS4; the middle portion of HPS1 (residues 250–505) is not required for this interaction. Further interaction studies showed that the N-termini of HPS1 and HPS4 interact with each other and that a discrete region of HPS4 (residues 340–528) interacts with both the N- and C-termini of the HPS1 protein. Several missense mutations found in HPS-1 patients did not affect interaction with HPS4, but some mutations involving regions interacting with HPS4 caused instability of HPS1. These observations extend our understanding of BLOC-3 assembly and represent an important first step in the identification of domains responsible for the biogenesis of lysosome-related organelles.
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hermansky pudlak syndrome type 3 in ashkenazi jews and other non puerto rican patients with hypopigmentation and platelet storage pool deficiency
American Journal of Human Genetics, 2001Co-Authors: Marjan Huizing, James G. White, Yair Anikster, Diana L Fitzpatrick, Anna B Jeong, Maria Dsouza, Melanie Rausche, Jorge R Toro, Muriel I Kaiserkupfer, William A. GahlAbstract:Hermansky-Pudlak syndrome (HPS), consisting of oculocutaneous albinism and a bleeding diathesis due to the absence of platelet dense granules, displays extensive locus heterogeneity. HPS1 mutations cause HPS-1 disease, and ADTB3A mutations cause HPS-2 disease, which is known to involve abnormal intracellular vesicle formation. A third HPS-causing gene, HPS3, was recently identified on the basis of homozygosity mapping of a genetic isolate of HPS in central Puerto Rico. We now describe the clinical and molecular characteristics of eight patients with HPS-3 who are of non–Puerto Rican heritage. Five are Ashkenazi Jews; three of these are homozygous for a 1303+1G→A splice-site mutation that causes skipping of exon 5, deleting an RsaI restriction site and decreasing the amounts of mRNA found on northern blotting. The other two are heterozygous for the 1303+1G→A mutation and for either an 1831+2T→G or a 2621-2A→G splicing mutation. Of 235 anonymous Ashkenazi Jewish DNA samples, one was heterozygous for the 1303+1G→A mutation. One seven-year-old boy of German/Swiss extraction was compound heterozygous for a 2729+1G→C mutation, causing skipping of exon 14, and resulting in a C1329T missense (R396W), with decreased mRNA production. A 15-year-old Irish/English boy was heterozygous for an 89-bp insertion between exons 16 and 17 resulting from abnormal splicing; his fibroblast HPS3 mRNA is normal in amount but is increased in size. A 12-year-old girl of Puerto Rican and Italian background has the 3,904-bp founder deletion from central Puerto Rico on one allele. All eight patients have mild symptoms of HPS; two Jewish patients had received the diagnosis of ocular, rather than oculocutaneous, albinism. These findings expand the molecular diagnosis of HPS, provide a screening method for a mutation common among Jews, and suggest that other patients with mild hypopigmentation and decreased vision should be examined for HPS.
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abnormal translocation of tyrosinase and tyrosinase related protein 1 in cutaneous melanocytes of hermansky pudlak syndrome and in melanoma cells transfected with anti sense hps1 cdna
Journal of Investigative Dermatology, 2001Co-Authors: Rangaprasad Sarangarajan, Ashish Budev, Yang Zhao, Raymond E. Boissy, William A. GahlAbstract:Hermansky–Pudlak syndrome is an autosomal recessive disorder characterized by oculocutaneous albinism, a bleeding disorder, and, in some patients, ceroid storage and progressive lung disease. Although Hermansky–Pudlak syndrome exhibits locus heterogeneity, most patients have mutations in the HPS1 gene. Melanocytes in the basal epithelial layer of skin from patients with different mutations in the HPS1 gene exhibited occasional large complexes containing dihydroxyphenylalanine-positive cisterna and 50 nm vesicles. To characterize the role of the HPS1 protein in cells, human HPS1 cDNA was transfected into pigmented SK-MEL-188 melanoma cells (M-188) in either the sense (S-188) or the antisense (A-188) orientation. Expression of the 79 kDa HPS1 protein (in M-188 and S-188 cells) or lack of expression (in A-188 cells) was confirmed by Western blotting using two HPS1-protein-specific polyclonal antibodies. Significant reduction in expression of HPS1 protein in A-188 cells resulted in a significant decrease in tyrosinase activity and melanin content compared with M-188 and S-188 cells using an intact cell assay for tyrosinase. In contrast, tyrosinase activities in cell lysates of M-188, S-188, and A-188 cells were not significantly different. Knockout of HPS1 protein expression in A-188 cells caused both tyrosinase and tyrosinase-related protein 1 to be localized to large granular complexes in the cell cytosol and dendrites. Electron microscope analysis of the A-188 cells revealed that absence of HPS1 protein resulted in the deposition of dihydroxyphenylalanine reaction products (i.e., tyrosinase) confined to large membrane-bound structures with limiting membranes. We conclude that lack of HPS1 protein expression results in mistranslocation of tyrosinase and tyrosinase-related protein 1 to large granular complexes rather than melanosomes, compromising melanin synthesis.
Carmelo Carmonarivera - One of the best experts on this subject based on the ideXlab platform.
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a divalent interaction between hps1 and hps4 is required for the formation of the biogenesis of lysosome related organelle complex 3 bloc 3
Biochimica et Biophysica Acta, 2013Co-Authors: William A. Gahl, Carmelo Carmonarivera, Dimitre R Simeonov, Nicholas D Cardillo, Carmen L CadillaAbstract:Abstract Hermansky–Pudlak syndrome (HPS) is a group of rare autosomal recessive disorders characterized by oculocutaneous albinism, a bleeding tendency, and sporadic pulmonary fibrosis, granulomatous colitis or infections. Nine HPS-causing genes have been identified in humans. HPS-1 is the most severe subtype with a prevalence of ~ 1/1800 in northwest Puerto Rico due to a founder mutation in the HPS1 gene. Mutations in HPS genes affect the biogenesis of lysosome-related organelles such as melanosomes in melanocytes and platelet dense granules. Two of these genes ( HPS1 and HPS4 ) encode the HPS1 and HPS4 proteins, which assemble to form a complex known as Biogenesis of Lysosome-related Organelle Complex 3 (BLOC-3). We report the identification of the interacting regions in HPS1 and HPS4 required for the formation of this complex. Two regions in HPS1, spanning amino acids 1–249 and 506–700 are required for binding to HPS4; the middle portion of HPS1 (residues 250–505) is not required for this interaction. Further interaction studies showed that the N-termini of HPS1 and HPS4 interact with each other and that a discrete region of HPS4 (residues 340–528) interacts with both the N- and C-termini of the HPS1 protein. Several missense mutations found in HPS-1 patients did not affect interaction with HPS4, but some mutations involving regions interacting with HPS4 caused instability of HPS1. These observations extend our understanding of BLOC-3 assembly and represent an important first step in the identification of domains responsible for the biogenesis of lysosome-related organelles.