Abstract
Mutations in the ABCC6 ABC-transporter are causative of pseudoxanthoma elasticum (PXE). The loss of functional ABCC6 protein in the basolateral membrane of the kidney and liver is putatively associated with altered secretion of a circulatory factor. As a result, systemic changes in elastic tissues are caused by progressive mineralization and degradation of elastic fibers. Premature arteriosclerosis, loss of skin and vascular tone, and a progressive loss of vision result from this ectopic mineralization. However, the identity of the circulatory factor and the specific role of ABCC6 in disease pathophysiology are not known. Though recessive loss-of-function alleles are associated with alterations in ABCC6 expression and function, the molecular pathologies associated with the majority of PXE-causing mutations are also not known. Sequence analysis of orthologous ABCC6 proteins indicates the C-terminal sequences are highly conserved and share high similarity to the PDZ sequences found in other ABCC subfamily members. Genetic testing of PXE patients suggests that at least one disease-causing mutation is located in a PDZ-like sequence at the extreme C-terminus of the ABCC6 protein. To evaluate the role of this C-terminal sequence in the biosynthesis and trafficking of ABCC6, a series of mutations were utilized to probe changes in ABCC6 biosynthesis, membrane stability and turnover. Removal of this PDZ-like sequence resulted in decreased steady-state ABCC6 levels, decreased cell surface expression and stability, and mislocalization of the ABCC6 protein in polarized cells. These data suggest that the conserved, PDZ-like sequence promotes the proper biosynthesis and trafficking of the ABCC6 protein.
Highlights
Pseudoxanthoma elasticum (PXE) is a disease characterized by the progressive mineralization of elastic fibers. [1,2] The mineralization and eventual degradation of these fibers cause a loss of elasticity in a variety of affected tissues
While the molecular mechanisms leading to the mineralization processes are unknown, mutations in the ABCC6 ATP-binding cassette (ABC-) transporter have been shown to be causative of the disease. [3,4] To date, more than 250 coding and noncoding mutations have been identified in ABCC6 that are associated with PXE. [5,6,7] The resulting loss of protein function in the basolateral membrane putatively alters the secretion of one or more unknown circulatory factors that systemically affect the mineralization of elastic fibers
C-terminally Regulated Trafficking of the ABCC6 Protein ABCC6 is a member of the ABC-transporter family of proteins and is composed of five domains (Figure 1A)
Summary
Pseudoxanthoma elasticum (PXE) is a disease characterized by the progressive mineralization of elastic fibers. [1,2] The mineralization and eventual degradation of these fibers cause a loss of elasticity in a variety of affected tissues. [19,20,21,22,23,24] The short C-terminal peptide sequences are bound by PDZ domain-containing proteins These multi-domain proteins facilitate protein-protein interactions by acting as scaffolds, binding their respective PDZ ligands and holding their partners in close physical proximity. These associations have been shown to regulate protein activity, protein stability and protein mobility in the membrane. Within the ABCC subfamily of human ABC-transporters, multiple PDZ ligands have been identified and characterized Alteration to these sequences results in mislocalization, reduced stability and increased mobility in other members of the ABCC subfamily, including the multi-drug transporters and CFTR [22,25,27,28,29]
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