| http://purl.uniprot.org/citations/27496948 | http://www.w3.org/1999/02/22-rdf-syntax-ns#type | http://purl.uniprot.org/core/Journal_Citation |
| http://purl.uniprot.org/citations/27496948 | http://www.w3.org/2000/01/rdf-schema#comment | "In eukaryotic cells, heme production is tightly controlled by heme itself through negative feedback-mediated regulation of nonspecific 5-aminolevulinate synthase (ALAS1), which is a rate-limiting enzyme for heme biosynthesis. However, the mechanism driving the heme-dependent degradation of the ALAS1 protein in mitochondria is largely unknown. In the current study, we provide evidence that the mitochondrial ATP-dependent protease ClpXP, which is a heteromultimer of CLPX and CLPP, is involved in the heme-dependent degradation of ALAS1 in mitochondria. We found that ALAS1 forms a complex with ClpXP in a heme-dependent manner and that siRNA-mediated suppression of either CLPX or CLPP expression induced ALAS1 accumulation in the HepG2 human hepatic cell line. We also found that a specific heme-binding motif on ALAS1, located at the N-terminal end of the mature protein, is required for the heme-dependent formation of this protein complex. Moreover, hemin-mediated oxidative modification of ALAS1 resulted in the recruitment of LONP1, another ATP-dependent protease in the mitochondrial matrix, into the ALAS1 protein complex. Notably, the heme-binding site in the N-terminal region of the mature ALAS1 protein is also necessary for the heme-dependent oxidation of ALAS1. These results suggest that ALAS1 undergoes a conformational change following the association of heme to the heme-binding motif on this protein. This change in the structure of ALAS1 may enhance the formation of complexes between ALAS1 and ATP-dependent proteases in the mitochondria, thereby accelerating the degradation of ALAS1 protein to maintain appropriate intracellular heme levels."xsd:string |
| http://purl.uniprot.org/citations/27496948 | http://purl.org/dc/terms/identifier | "doi:10.1074/jbc.m116.719161"xsd:string |
| http://purl.uniprot.org/citations/27496948 | http://purl.uniprot.org/core/author | "Kubota Y."xsd:string |
| http://purl.uniprot.org/citations/27496948 | http://purl.uniprot.org/core/author | "Nomura K."xsd:string |
| http://purl.uniprot.org/citations/27496948 | http://purl.uniprot.org/core/author | "Katoh Y."xsd:string |
| http://purl.uniprot.org/citations/27496948 | http://purl.uniprot.org/core/author | "Yamashita R."xsd:string |
| http://purl.uniprot.org/citations/27496948 | http://purl.uniprot.org/core/author | "Kaneko K."xsd:string |
| http://purl.uniprot.org/citations/27496948 | http://purl.uniprot.org/core/author | "Furuyama K."xsd:string |
| http://purl.uniprot.org/citations/27496948 | http://purl.uniprot.org/core/date | "2016"xsd:gYear |
| http://purl.uniprot.org/citations/27496948 | http://purl.uniprot.org/core/name | "J Biol Chem"xsd:string |
| http://purl.uniprot.org/citations/27496948 | http://purl.uniprot.org/core/pages | "20516-20529"xsd:string |
| http://purl.uniprot.org/citations/27496948 | http://purl.uniprot.org/core/title | "Novel Mechanisms for Heme-dependent Degradation of ALAS1 Protein as a Component of Negative Feedback Regulation of Heme Biosynthesis."xsd:string |
| http://purl.uniprot.org/citations/27496948 | http://purl.uniprot.org/core/volume | "291"xsd:string |
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