(NAS Colloquium) Proteolytic Processing and Physiological Regulation (1999) / Chapter Skim
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A proteolytic pathway that controls the cholesterol content of membranes, cells, and blood
A proteolytic pathway that controls the cholesterol content of membranes, cells, and blood
Pages 11041-11048
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From page 11041... ...
19~. In the cholesterol biosynthetic pathway, well defined target genes include HMG-CoA synthase, HMG-CoA Abbreviations: bHLH-Zip, basic-helix-loop-helix-leucine zipper; CHO, Chinese hamster ovary; ER, endoplasmic reticulum; HMG CoA, 3-hydroxy-3-methylglutaryl CoA; LDL, low density lipoprotein; PLAP, placental alkaline phosphatase; SRE, sterol regulatory ele ment; SREBP, sterol regulatory element-binding protein; SCAP, SREBP cleavage-activating protein; SIP; Site-1 protease; S2P; Site-2 protease.
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From page 11042... ...
The SREBPs also enhance transcription of the LDL receptor, which mediates cholesterol uptake from plasma lipoproteins. Overexpression of the NH2-terminal nuclear domains of SREBPs also elevates mRNAs encoding many other enzymes required for lipid synthesis, including enzymes that generate acetyl CoA and reduced pyridine nucleotides (21~.
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From page 11043... ...
Class 2 mutants produce normal full-length SREBP-1 and SREBP-2 and proteolyze them normally, but they cannot turn off proteolysis in response to sterol overload. We identified the defective gene in the Class 2 mutants by preparing a cDNA library from one of the mutant cell lines, transfecting pools of cDNAs into cultured human embryonic kidney 293 cells, and assaying for a relief of the oxysterol-dependent inhibition of expression of a reporter gene driven by an SRE-containing promoter.
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From page 11044... ...
The first of these, termed S2P, was isolated from a mutant line of CHO cells that is unable to produce LDL receptors, cholesterol biosynthetic enzymes, or fatty acid desaturases (43~. The molecular defect was traced to a specific inability to carry out Site-2 cleavage of SREBPs (18, 444.
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From page 11045... ...
51. In brief, the plasmid was generated by fusing the sequence encoding the signal peptide and soluble catalytic domain of human placental alkaline phosphatase (amino acids 1-506)
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From page 11046... ...
Subtilisin-re l ate d enzymes , or subtil ases , are s erine pro teases that contain a catalytic site with the classic triad of serine, aspartic acid, and histidine residues as well as a remote asparagine that contributes to a so-called oxyanion hole (52~. Although they share the catalytic triad with the other large family of serine proteases, the trypsin-like enzymes, the subtilases are believed to have evolved independently.
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From page 11047... ...
SIP is the first vertebrate subtilisin whose sequence more closely resembles the bacterial members of this family as compared with the mammalian members. This finding is consistent with the observation that SIP cleaves SREBP after a hydrophobic leucine residue rather than after a basic residue.
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From page 11048... ...
11048 Colloquium Paper: Brown and Goldstein 56. Nagase, T., Miyajima, N., Tanaka, A., Sazuka, T., Seki, N., Sato, S., Tabata, S., Ishikawa.
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