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Herbert J. Kayden - One of the best experts on this subject based on the ideXlab platform.
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Localization of alpha-tocopherol transfer protein in the brains of patients with ataxia with vitamin E deficiency and other oxidative stress related neurodegenerative disorders.
Brain research, 1999Co-Authors: R P Copp, A Larnaout, M Ben Hamida, Fayçal Hentati, T Wisniewski, Herbert J. KaydenAbstract:Vitamin E (alpha-tocopherol) is an essential nutrient and an important antioxidant. Its plasma levels are dependent upon oral intake, absorption and transfer of the vitamin to a circulating lipoprotein. The latter step is controlled by alpha-tocopherol transfer protein (alpha-TTP), which is a 278 amino acid protein encoded on chromosome 8, known to be synthesized in the liver. Mutations in alpha-TTP are associated with a neurological syndrome of spinocerebellar ataxia, called ataxia with vitamin E deficiency (AVED). Earlier studies suggested that alpha-TTP is found only in the liver. In order to establish whether alpha-TTP is expressed in the human brain, and what relationship this has to AVED, we studied immunohistochemically the presence of alpha-TTP in the brains of a patient with AVED, normal subjects, and patients with Alzheimer's disease (AD), Down's syndrome (DS), cholestatic liver disease (CLD) and Abetalipoproteinemia (ABL). The neuropathology of both AD and DS is thought to be related in part to oxidative stress. The diseases of AVED, of cholestatic liver disease, and of Abetalipoproteinemia are thought to be due to lack of circulating tocopherol, leading to inadequate protection against oxidative damage. We demonstrate the presence of alpha-TTP in cerebellar Purkinje cells in patients having vitamin E deficiency states or diseases associated with oxidative stress.
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localization of α tocopherol transfer protein in the brains of patients with ataxia with vitamin e deficiency and other oxidative stress related neurodegenerative disorders
Brain Research, 1999Co-Authors: R P Copp, A Larnaout, Fayçal Hentati, T Wisniewski, Ben M Hamida, Herbert J. KaydenAbstract:Vitamin E (alpha-tocopherol) is an essential nutrient and an important antioxidant. Its plasma levels are dependent upon oral intake, absorption and transfer of the vitamin to a circulating lipoprotein. The latter step is controlled by alpha-tocopherol transfer protein (alpha-TTP), which is a 278 amino acid protein encoded on chromosome 8, known to be synthesized in the liver. Mutations in alpha-TTP are associated with a neurological syndrome of spinocerebellar ataxia, called ataxia with vitamin E deficiency (AVED). Earlier studies suggested that alpha-TTP is found only in the liver. In order to establish whether alpha-TTP is expressed in the human brain, and what relationship this has to AVED, we studied immunohistochemically the presence of alpha-TTP in the brains of a patient with AVED, normal subjects, and patients with Alzheimer's disease (AD), Down's syndrome (DS), cholestatic liver disease (CLD) and Abetalipoproteinemia (ABL). The neuropathology of both AD and DS is thought to be related in part to oxidative stress. The diseases of AVED, of cholestatic liver disease, and of Abetalipoproteinemia are thought to be due to lack of circulating tocopherol, leading to inadequate protection against oxidative damage. We demonstrate the presence of alpha-TTP in cerebellar Purkinje cells in patients having vitamin E deficiency states or diseases associated with oxidative stress.
R P Copp - One of the best experts on this subject based on the ideXlab platform.
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Localization of alpha-tocopherol transfer protein in the brains of patients with ataxia with vitamin E deficiency and other oxidative stress related neurodegenerative disorders.
Brain research, 1999Co-Authors: R P Copp, A Larnaout, M Ben Hamida, Fayçal Hentati, T Wisniewski, Herbert J. KaydenAbstract:Vitamin E (alpha-tocopherol) is an essential nutrient and an important antioxidant. Its plasma levels are dependent upon oral intake, absorption and transfer of the vitamin to a circulating lipoprotein. The latter step is controlled by alpha-tocopherol transfer protein (alpha-TTP), which is a 278 amino acid protein encoded on chromosome 8, known to be synthesized in the liver. Mutations in alpha-TTP are associated with a neurological syndrome of spinocerebellar ataxia, called ataxia with vitamin E deficiency (AVED). Earlier studies suggested that alpha-TTP is found only in the liver. In order to establish whether alpha-TTP is expressed in the human brain, and what relationship this has to AVED, we studied immunohistochemically the presence of alpha-TTP in the brains of a patient with AVED, normal subjects, and patients with Alzheimer's disease (AD), Down's syndrome (DS), cholestatic liver disease (CLD) and Abetalipoproteinemia (ABL). The neuropathology of both AD and DS is thought to be related in part to oxidative stress. The diseases of AVED, of cholestatic liver disease, and of Abetalipoproteinemia are thought to be due to lack of circulating tocopherol, leading to inadequate protection against oxidative damage. We demonstrate the presence of alpha-TTP in cerebellar Purkinje cells in patients having vitamin E deficiency states or diseases associated with oxidative stress.
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localization of α tocopherol transfer protein in the brains of patients with ataxia with vitamin e deficiency and other oxidative stress related neurodegenerative disorders
Brain Research, 1999Co-Authors: R P Copp, A Larnaout, Fayçal Hentati, T Wisniewski, Ben M Hamida, Herbert J. KaydenAbstract:Vitamin E (alpha-tocopherol) is an essential nutrient and an important antioxidant. Its plasma levels are dependent upon oral intake, absorption and transfer of the vitamin to a circulating lipoprotein. The latter step is controlled by alpha-tocopherol transfer protein (alpha-TTP), which is a 278 amino acid protein encoded on chromosome 8, known to be synthesized in the liver. Mutations in alpha-TTP are associated with a neurological syndrome of spinocerebellar ataxia, called ataxia with vitamin E deficiency (AVED). Earlier studies suggested that alpha-TTP is found only in the liver. In order to establish whether alpha-TTP is expressed in the human brain, and what relationship this has to AVED, we studied immunohistochemically the presence of alpha-TTP in the brains of a patient with AVED, normal subjects, and patients with Alzheimer's disease (AD), Down's syndrome (DS), cholestatic liver disease (CLD) and Abetalipoproteinemia (ABL). The neuropathology of both AD and DS is thought to be related in part to oxidative stress. The diseases of AVED, of cholestatic liver disease, and of Abetalipoproteinemia are thought to be due to lack of circulating tocopherol, leading to inadequate protection against oxidative damage. We demonstrate the presence of alpha-TTP in cerebellar Purkinje cells in patients having vitamin E deficiency states or diseases associated with oxidative stress.
Lawrence P. Aggerbeck - One of the best experts on this subject based on the ideXlab platform.
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apolipoprotein b48 glycosylation in Abetalipoproteinemia and anderson s disease
Gastroenterology, 2001Co-Authors: Nathalie Berriotvaroqueaux, J Schmitz, Agnes Sassolas, Hayssam A Dannoura, Alain Moreau, Nicole Verthier, Guillaume Cadiot, A Lachaux, A Munck, Lawrence P. AggerbeckAbstract:Abstract Background & Aims: Abetalipoproteinemia and Anderson's disease are hereditary lipid malabsorption syndromes. In Abetalipoproteinemia, lipoprotein assembly is defective because of mutations in the microsomal triglyceride transfer protein. Here, we evaluated the intracellular transport of apolipoprotein B48 to localize the defect in Anderson's disease. Methods: Asparagine-linked oligosaccharide processing of apolipoprotein B48 in normal and affected individuals was determined by the endoglycosidase H and F sensitivities of the protein after metabolic labeling of intestinal explants in organ culture. Cell ultrastructure was evaluated with electron microscopy. Results: In Anderson's disease as in normal individuals, there was a time-dependent transformation of high mannose endoglycosidase H–sensitive oligosaccharides, of endoplasmic reticulum origin, to complex endoglycosidase H–resistant oligosaccharides, added in the Golgi network. In contrast, despite the translocation of apolipoprotein B48 into the endoplasmic reticulum in patients with Abetalipoproteinemia and in biopsies treated with Brefeldin A, which blocks anterograde transport between the endoplasmic reticulum and the Golgi network, there was no transformation of endoglycosidase H–sensitive oligosaccharides. Conclusions: In Abetalipoproteinemia and Anderson's disease, apolipoprotein B48 is completely translocated into the endoplasmic reticulum, but only in Anderson's disease is the protein transported to the Golgi apparatus. This suggests that Anderson's disease is caused by a post-Golgi cargo-specific secretion defect. GASTROENTEROLOGY 2001;121:1101-1108
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The role of the microsomal triglygeride transfer protein in Abetalipoproteinemia.
Annual review of nutrition, 2000Co-Authors: Nathalie Berriot-varoqueaux, Lawrence P. Aggerbeck, M.-e. Samson-bouma, J. R. WetterauAbstract:The microsomal triglyceride transfer protein (MTP) is a dimeric lipid transfer protein consisting of protein disulfide isomerase and a unique 97-kDa subunit. In vitro, MTP accelerates the transport of triglyceride, cholesteryl ester, and phospholipid between membranes. It was recently demonstrated that Abetalipoproteinemia, a hereditary disease characterized as an inability to produce chylomicrons and very low-density lipoproteins in the intestine and liver, respectively, results from mutations in the gene encoding the 97-kDa subunit of the microsomal triglyceride transfer protein. Downstream effects resulting from this defect include malnutrition, very low plasma cholesterol and triglyceride levels, altered lipid and protein compositions of membranes and lipoprotein particles, and vitamin deficiencies. Unless treated, abetalipoproteinemic subjects develop gastrointestinal, neurological, ophthalmological, and hematological abnormalities.
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Microsomal triglyceride transfer protein and Abetalipoproteinemia
Annales d'endocrinologie, 2000Co-Authors: Nathalie Berriot-varoqueaux, Lawrence P. Aggerbeck, M.-e. Samson-boumaAbstract:Microsomal triglyceride transfer protein (MTP) is a dimeric protein complex consisting of protein disulfide isomerase and a unique 97 kDa subunit. In vitro, MTP accelerates the transport of triglyceride, cholesteryl ester, and phospholipid between vesicles. It was recently demonstrated that Abetalipoproteinemia, a disease characterized as an inability to produce chylomicrons and very low density lipoproteins in the intestine and liver, respectively, is the result of a genetic absence of MTP. Downstream effects resulting from this defect, include very low plasma cholesterol and triglyceride levels, absence of plasma apolipoprotein B and a lipid malabsorption syndrome, leading to lipo-soluble vitamin deficiencies. A low fat diet is instituted to eliminate the diarrhea. In addition, a therapy with vitamins A and E is essential to prevent patients from developing secondary effects such as neuropathy, muscle weakness, and retinopathy.
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a novel Abetalipoproteinemia genotype identification of a missense mutation in the 97 kda subunit of the microsomal triglyceride transfer protein that prevents complex formation with protein disulfide isomerase
Journal of Biological Chemistry, 1996Co-Authors: Edward F Rehberg, Lawrence P. Aggerbeck, Bernadette Kienzle, Laura Blinderman, John R. Wetterau, Marieelisabeth Samsonbouma, Haris Jamil, David A GordonAbstract:The microsomal triglyceride transfer protein (MTP) is a heterodimer composed of the ubiquitous multifunctional protein, protein disulfide isomerase, and a unique 97-kDa subunit. Mutations that lead to the absence of a functional 97-kDa subunit cause Abetalipoproteinemia, an autosomal recessive disease characterized by a defect in the assembly and secretion of apolipoprotein B (apoB) containing lipoproteins. Previous studies of abetalipoproteinemic patient, C.L., showed that the 97-kDa subunit was undetectable. In this report, [35S]methionine labeling showed that this tissue was capable of synthesizing the 97-kDa MTP subunit. Electrophoretic analysis showed two bands, one with a molecular mass of the wild type 97-kDa subunit and the other with a slightly lower molecular weight. Sequence analysis of cDNAs from additional intestinal biopsies showed this patient to be a compound heterozygote. One allele contained a perfect in-frame deletion of exon 10, explaining the lower molecular weight band. cDNAs of the second allele were found to contain 3 missense mutations: His297 --> Gln, Asp384 --> Ala, and Arg540 --> His. Transient expression of each mutant showed that only the Arg540 --> His mutant was non-functional based upon its inability to reconstitute apoB secretion in a cell culture system. The other amino acid changes are silent polymorphisms. High level coexpression in a baculovirus system of the wild type 97-kDa subunit or the Arg540 --> His mutant along with human protein disulfide isomerase showed that the wild type was capable of forming an active MTP complex while the mutant was not. Biochemical analysis of lysates from these cells showed that the Arg to His conversion interrupted the interaction between the 97-kDa subunit and protein disulfide isomerase. Replacement of Arg540 with a lysine residue maintained the ability of the 97-kDa subunit to complex with protein disulfide isomerase and form the active MTP holoprotein. These results indicate that a positively charged amino acid at position 540 in the 97-kDa subunit is critical for the productive association with protein disulfide isomerase. Of the 13 mutant MTP 97-kDa subunit alleles described to date, this is the first encoding a missense mutation.
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Absence of microsomal triglyceride transfer protein in individuals with Abetalipoproteinemia
Science (New York N.Y.), 1992Co-Authors: Wetterau, Lawrence P. Aggerbeck, M.e. Bouma, J Schmitz, A Munck, C Eisenberg, M Hermier, Daniel J. Rader, R E GreggAbstract:Abetalipoproteinemia is a human genetic disease that is characterized by a defect in the assembly or secretion of plasma very low density lipoproteins and chylomicrons. The microsomal triglyceride transfer protein (MTP), which is located in the lumen of microsomes isolated from the liver and intestine, has been proposed to function in lipoprotein assembly. MTP activity and the 88-kilodalton component of MTP were present in intestinal biopsy samples from eight control individuals but were absent in four abetalipoproteinemic subjects. This finding suggests that a defect in MTP is the basis for Abetalipoproteinemia and that MTP is indeed required for lipoprotein assembly.
Agnes Sassolas - One of the best experts on this subject based on the ideXlab platform.
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RESEARCH Open Access Molecular characterization of Tunisian families
2014Co-Authors: Mohamed Najah, Agnes Sassolas, Sarraj Mohamed Youssef, Hrira Mohamed Yahia, Slimani Afef, Jelassi Awatef, Hammami Saber, Najjar Mohamed Fadhel, Slimane Mohamed NaceurAbstract:with Abetalipoproteinemia and identification of a novel mutation in MTTP gen
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Molecular characterization of Tunisian families with Abetalipoproteinemia and identification of a novel mutation in MTTP gene
Diagnostic Pathology, 2013Co-Authors: Mohamed Najah, Agnes Sassolas, Sarraj Mohamed Youssef, Hrira Mohamed Yahia, Slimani Afef, Jelassi Awatef, Hammami Saber, Najjar Mohamed Fadhel, Slimane Mohamed NaceurAbstract:Background Abetalipoproteinemia (ABL; OMIM 200100) is a rare monogenic disorder of lipid metabolism characterized by reduced plasma levels of total cholesterol (TC), low density lipoprotein-cholesterol (LDL-C) and almost complete absence of apolipoprotein B (apoB). ABL results from genetic deficiency in microsomal triglyceride transfer protein (MTP; OMIM 157147). In the present study we investigated two unrelated Tunisian patients, born from consanguineous marriages, with severe deficiency of plasma low-density lipoprotein (LDL) and apo B. Methods Intestinal biopsies were performed and The MTTP gene was amplified by Polymerase chain reaction then directly sequenced in patients presenting chronic diarrhea and retarded growth. Results First proband was homozygous for a novel nucleotide deletion (c. 2611delC) involving the exon 18 of MTTP gene predicted to cause a non functional protein of 898 amino acids (p.H871I fsX29). Second proband was homozygous for a nonsense mutation in exon 8 (c.923 G > A) predicted to cause a truncated protein of 307 amino acids (p.W308X), previously reported in ABL patients. Conclusions We discovered a novel mutation in MTTP gene and we confirmed the diagnosis of Abetalipoproteinemia in new Tunisian families. Virtual slides The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/8134027928652779 .
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Molecular characterization of Tunisian families with Abetalipoproteinemia and identification of a novel mutation in MTTP gene
Diagnostic pathology, 2013Co-Authors: Mohamed Najah, Agnes Sassolas, Sarraj Mohamed Youssef, Hrira Mohamed Yahia, Slimani Afef, Jelassi Awatef, Hammami Saber, Najjar Mohamed Fadhel, Slimane Mohamed NaceurAbstract:Background Abetalipoproteinemia (ABL; OMIM 200100) is a rare monogenic disorder of lipid metabolism characterized by reduced plasma levels of total cholesterol (TC), low density lipoprotein-cholesterol (LDL-C) and almost complete absence of apolipoprotein B (apoB). ABL results from genetic deficiency in microsomal triglyceride transfer protein (MTP; OMIM 157147). In the present study we investigated two unrelated Tunisian patients, born from consanguineous marriages, with severe deficiency of plasma low-density lipoprotein (LDL) and apo B.
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A severe form of Abetalipoproteinemia caused by new splicing mutations of microsomal triglyceride transfer protein
Human Mutation, 2011Co-Authors: Véronique Pons, Agnes Sassolas, Corinne Rolland, Michel Nauze, Marie Danjoux, Gérald Gaibelet, Anne H. Durandy, Emile Lévy, François Tercé, Xavier ColletAbstract:Abetalipoproteinemia is a rare autosomal recessive disease characterized by low lipid levels and by the absence of apoB-containing lipoproteins. It is the consequence of microsomal triglyceride transfer protein (MTTP) deficiency. We report 2 patients with new MTTP mutations. We studied their functional consequences on the triglyceride transfer function using duodenal biopsies. We transfected MTTP mutants in HepG2 and HeLa cells to investigate their association with protein disulfide isomerase (PDI) and their localization at the endoplasmic reticulum. These children have a severe Abetalipoproteinemia. Both of them had also a mild hypogammaglobulinemia. They are compound heterozygotes with c.619G>T and c.1237-28A>G mutations within MTTP gene. mRNA analysis revealed abnormal splicing with deletion of exon 6 and 10, respectively. Deletion of exon 6 (Δ6-MTTP) introduced a frame shift in the reading frame and a premature stop codon at position 234. Despite Δ6-MTTP and Δ10-MTTP mutants were not capable of binding PDI, both MTTP mutant proteins normally localize at the endoplasmic reticulum. However, these two mutations induce a loss of MTTP triglyceride transfer activity. These two mutations lead to abnormal truncated MTTP proteins, incapable of binding PDI and responsible for the loss of function of MTTP, thereby explaining the severe Abetalipoproteinemia phenotype of these children.
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guidelines for the diagnosis and management of chylomicron retention disease based on a review of the literature and the experience of two centers
Orphanet Journal of Rare Diseases, 2010Co-Authors: Noël Peretti, Colette Deslandres, Agnes Sassolas, Mathilde Charcosset, Justine Castagnetti, Laurence Pugnetchardon, Philippe Moulin, Sylvie LabargeAbstract:Familial hypocholesterolemia, namely Abetalipoproteinemia, hypobetalipoproteinemia and chylomicron retention disease (CRD), are rare genetic diseases that cause malnutrition, failure to thrive, growth failure and vitamin E deficiency, as well as other complications. Recently, the gene implicated in CRD was identified. The diagnosis is often delayed because symptoms are nonspecific. Treatment and follow-up remain poorly defined.
David A Gordon - One of the best experts on this subject based on the ideXlab platform.
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a novel Abetalipoproteinemia genotype identification of a missense mutation in the 97 kda subunit of the microsomal triglyceride transfer protein that prevents complex formation with protein disulfide isomerase
Journal of Biological Chemistry, 1996Co-Authors: Edward F Rehberg, Lawrence P. Aggerbeck, Bernadette Kienzle, Laura Blinderman, John R. Wetterau, Marieelisabeth Samsonbouma, Haris Jamil, David A GordonAbstract:The microsomal triglyceride transfer protein (MTP) is a heterodimer composed of the ubiquitous multifunctional protein, protein disulfide isomerase, and a unique 97-kDa subunit. Mutations that lead to the absence of a functional 97-kDa subunit cause Abetalipoproteinemia, an autosomal recessive disease characterized by a defect in the assembly and secretion of apolipoprotein B (apoB) containing lipoproteins. Previous studies of abetalipoproteinemic patient, C.L., showed that the 97-kDa subunit was undetectable. In this report, [35S]methionine labeling showed that this tissue was capable of synthesizing the 97-kDa MTP subunit. Electrophoretic analysis showed two bands, one with a molecular mass of the wild type 97-kDa subunit and the other with a slightly lower molecular weight. Sequence analysis of cDNAs from additional intestinal biopsies showed this patient to be a compound heterozygote. One allele contained a perfect in-frame deletion of exon 10, explaining the lower molecular weight band. cDNAs of the second allele were found to contain 3 missense mutations: His297 --> Gln, Asp384 --> Ala, and Arg540 --> His. Transient expression of each mutant showed that only the Arg540 --> His mutant was non-functional based upon its inability to reconstitute apoB secretion in a cell culture system. The other amino acid changes are silent polymorphisms. High level coexpression in a baculovirus system of the wild type 97-kDa subunit or the Arg540 --> His mutant along with human protein disulfide isomerase showed that the wild type was capable of forming an active MTP complex while the mutant was not. Biochemical analysis of lysates from these cells showed that the Arg to His conversion interrupted the interaction between the 97-kDa subunit and protein disulfide isomerase. Replacement of Arg540 with a lysine residue maintained the ability of the 97-kDa subunit to complex with protein disulfide isomerase and form the active MTP holoprotein. These results indicate that a positively charged amino acid at position 540 in the 97-kDa subunit is critical for the productive association with protein disulfide isomerase. Of the 13 mutant MTP 97-kDa subunit alleles described to date, this is the first encoding a missense mutation.
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a 30 amino acid truncation of the microsomal triglyceride transfer protein large subunit disrupts its interaction with protein disulfide isomerase and causes Abetalipoproteinemia
Journal of Biological Chemistry, 1995Co-Authors: Beverly Ricci, Richard E. Gregg, Daru Young Sharp, Edward Orourke, Bernadette Kienzle, Laura Blinderman, David A Gordon, Connie Smithmonroy, Gordon William Robinson, Daniel J. RaderAbstract:The microsomal triglyceride transfer protein (MTP) is a heterodimer composed of the multifunctional enzyme, protein disulfide-isomerase, and a unique large, 97 kDa, subunit. It is found as a soluble protein within the lumen of the endoplasmic reticulum of liver and intestine and is required for the assembly of very low density lipoproteins and chylomicrons. Mutations in MTP which result in an absence of MTP function have been shown to cause Abetalipoproteinemia. Here, the gene encoding the MTP 97-kDa subunit of an abetalipoproteinemic subject, which we have previously demonstrated lacks MTP activity and protein (Wetterau, J. R., Aggerbeck, L. P., Bouma, M.-E., Eisenberg, C., Munck, A., Hermier, M., Schmitz, J., Gay, G., Rader, D. J., and Gregg, R. E.(1992) Science 258, 999-1001), was isolated and sequenced. A nonsense mutation, which predicts the truncation of the protein by 30 amino acids, was identified. To investigate if this apparently subtle change in MTP could explain the observed absence of MTP, protein disulfide-isomerase was co-expressed with either the normal or mutant MTP 97-kDa subunit in Sf9 insect cells using a baculovirus expression system. Although there were high levels of expression of both the normal and mutant forms of the MTP 97-kDA subunit, only the normal subunit was able to form a stable, soluble complex with protein disulfide-isomerase. These results indicate that the carboxyl-terminal 30 amino acids of the MTP 97-kDa subunit plays an important role in its interaction with protein disulfide-isomerase.
