The inhibition of degradation of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase by sterol regulatory element binding protein cleavage-activating protein requires four phenylalanine residues in span 6 of HMG-CoA reductase transmembrane domain

Autor: Liwen Xu, Robert D. Simoni
Rok vydání: 2003
Předmět:
DNA
Complementary
Time Factors
Phenylalanine
Coenzyme A
Molecular Sequence Data
Biophysics
Golgi Apparatus
CHO Cells
Reductase
Transfection
Biochemistry
chemistry.chemical_compound
Cricetinae
polycyclic compounds
Animals
Humans
Amino Acid Sequence
Enzyme Inhibitors
Molecular Biology
chemistry.chemical_classification
Endoplasmic reticulum membrane
Dose-Response Relationship
Drug
Sequence Homology
Amino Acid
biology
Cell Membrane
beta-Galactosidase
Farnesol
Protein Structure
Tertiary
Sterol regulatory element-binding protein
DNA-Binding Proteins
Sterols
Cytosol
Transmembrane domain
Enzyme
chemistry
HMG-CoA reductase
CCAAT-Enhancer-Binding Proteins
Mutagenesis
Site-Directed
biology.protein
Hydroxymethylglutaryl CoA Reductases
lipids (amino acids
peptides
and proteins)
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Sterol Regulatory Element Binding Protein 1
Plasmids
Protein Binding
Transcription Factors
Zdroj: Archives of Biochemistry and Biophysics. 414:232-243
ISSN: 0003-9861
DOI: 10.1016/s0003-9861(03)00168-1
Popis: 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR) is the rate-limiting enzyme in the cholesterol biosynthetic pathway. This endoplasmic reticulum membrane protein contains a cytosolic catalytic domain and a transmembrane domain with eight membrane spans that are necessary for sterol-accelerated degradation. Competition experiments showed that wild-type transmembrane domains of HMGR and sterol regulatory element binding protein cleavage-activating protein (SCAP) blocked sterol-accelerated degradation of intact HMGR and HMGal, a model protein containing the membrane domain of HMGR linked to Escherichia coli beta-galactosidase. However, mutant transmembrane domains of HMGR and SCAP whose sterol-sensing functions were abolished did not inhibit sterol-accelerated degradation of HMGR and HMGal. In addition, our mutagenesis studies on HMGal indicated that four Phe residues conserved in span 6 of HMGR and the sterol-sensing domains of other sterol-related proteins are required for the regulated degradation of HMGR. These results suggest that HMGR and SCAP compete for binding to a sterol-regulated regulator protein, and this binding may need the four Phe residues.
Databáze: OpenAIRE
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