16 - BCH 3120 lipid and amino acid metabolism zemin yao...

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zemin yao professor and chair biochemistry, microbiology & immunology e-mail: [email protected] BCH 3120 lipid and amino acid metabolism 03-09-11, Wed. 08:30-10:00 08:30-10:00 am
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mutations within LDLR that cause familial hypercholesterolemia (I) 1. LDLR-null - mutations within exon 1 of the LDLR gene resulting the lack of protein synthesis (French Canadians) 2. ER/Golgi trafficking – mutations causing retention of LDLR within the ER and not transported to the plasma membrane 3. ligand-binding – mutations within the ligand-binding domain resulting in impaired binding to LDL (apoB100) 4. internalization – mutations with the intracellular domain of LDLR resulting in inability to internalize LDLR/LDL complex
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amino acids coated vesicle lysosome endosome N sorting and recycling of LDLR cholesterol fatty acids ‘coat’ 5
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mutations within LDLR that cause familial hypercholesterolemia (II) 5. LDLR recycling – mutations preventing dissociation of LDLR/LDL complex within the “sorting” endosome and not allowing LDLR recycle back to the plasma membrane
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N cholesterol summary: five stages affecting the LDLR function lysosome endosome sorting endosome recycling endosome 1 2 4 3 5
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familial hypercholesterolemia an autosomal co-dominant disorder characterized by elevated plasma LDL concentrations and premature atherosclerosis loss-of-function mutations within the LDLR gene is the most prevalent cause of hypercholesterolemia the allele frequency for LDLR mutation is high: 1/500 in general population more frequent among certain ethnic groups (e.g. French-Canadians, Afrikaners, Lebanese)
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cutaneous xanthoma in FH patients
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today’s lecture regulation of the mevalonate pathway regulation of the LDL receptor pathway the SREBP/SCAP/INSIG axis
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N SREBP-2 is an “ER residence” protein LDLR ER SREBP-2 ?
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migration of SREBP-2 into nucleus Q1: what is the mechanism that cleaves SREBP-2 on the membrane? Q2: how do the cells know when the SREBP-2 should be cleaved? Q3: does SREBP-2 contain a “sensing mechanism” to detect cholesterol concentrations in the cells?
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A1: SREBP-2 is cleaved by endopeptidases in the Golgi apparatus N bHLH regul at ory cytoplasm Golgi lumen C cleavage 1 cleavage 2 ER Golgi N
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ER Golgi N A2: SREBP-2 is transported from ER to Golgi when cholesterol level is low
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migration of SREBP-2 into nucleus Q1: what is the mechanism that cleaves SREBP-2 on the membrane? Q2: how do the cells know when the SREBP-2 should be cleaved? Q3: does SREBP-2 contain a “sensing mechanism” to detect cholesterol concentrations in the cells?
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ER Golgi SREBP-2 exits ER via vesicles coat proteins (COP-II)
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SCAP escorts SREBP to Golgi when cholesterol level is low ER Golgi SCAP
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migration of SREBP-2 into nucleus Q1: what is the mechanism that cleaves SREBP-2 on the membrane?
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