6bzs | pdb_00006bzs
Human ABCC6 NBD1 in Apo state
Structural highlights
DiseaseMRP6_HUMAN Generalized arterial calcification of infancy;Pseudoxanthoma elasticum. The disease is caused by mutations affecting the gene represented in this entry. Homozygous or compound heterozygous ABCC6 mutations have been found in the overwhelming majority of cases. Individuals carrying heterozygous mutations express limited manifestations of the pseudoxanthoma elasticum phenotype. The disease is caused by mutations affecting the gene represented in this entry. FunctionMRP6_HUMAN Isoform 1: May participate directly in the active transport of drugs into subcellular organelles or influence drug distribution indirectly. Transports glutathione conjugates as leukotriene-c4 (LTC4) and N-ethylmaleimide S-glutathione (NEM-GS).[1] Isoform 2: Inhibits TNF-alpha-mediated apoptosis through blocking one or more caspases.[2] Publication Abstract from PubMedMutations in ATP-binding cassette subfamily C member 6 (ABCC6) transporter are associated with pseudoxanthoma elasticum (PXE), a disease resulting in ectopic mineralization and affecting multiple tissues. A growing number of mutations have been identified in individuals with PXE. For most of these variants, no mechanistic information is available regarding their role in normal and pathophysiologies. To assess how PXE-associated mutations alter ABCC6 biosynthesis and structure, we biophysically and biochemically evaluated the N-terminal nucleotide-binding domain of ABCC6. A high-resolution X-ray structure of nucleotide-binding domain 1 (NBD1) of human ABCC6 was obtained at 2.3 A that provided a template on which to evaluate PXE-causing mutations. Biochemical analysis of mutations in this domain indicated that multiple PXE-causing mutations altered its structural properties. Analyses of the full-length protein revealed a strong correlation between the alterations in NBD properties and the processing and expression of ABCC6. These results suggest that a significant fraction of PXE-associated mutations located in NBD1 causes changes in its structural properties and that these mutation-induced alterations directly affect the maturation of the full-length ABCC6 protein. Structural analysis reveals pathomechanisms associated with pseudoxanthoma elasticum-causing mutations in the ABCC6 transporter.,Ran Y, Zheng A, Thibodeau PH J Biol Chem. 2018 Aug 28. pii: RA118.004806. doi: 10.1074/jbc.RA118.004806. PMID:30154241[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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