ABCMdb

ABCC6 p.Asn15Asp

Predicted by SNAP2:	A: D (75%), C: D (71%), D: N (82%), E: D (85%), F: D (80%), G: D (66%), H: D (75%), I: D (75%), K: D (80%), L: D (80%), M: D (80%), P: D (85%), Q: D (75%), R: D (85%), S: D (71%), T: D (75%), V: D (80%), W: D (75%), Y: D (80%),
Predicted by PROVEAN:	A: D, C: D, D: N, E: N, F: D, G: D, H: N, I: D, K: D, L: D, M: D, P: D, Q: D, R: D, S: N, T: D, V: D, W: D, Y: D,

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Publications
[hide] Regulation of ABCC6 trafficking and stability by a... PLoS One. 2014 May 19;9(5):e97360. doi: 10.1371/journal.pone.0097360. eCollection 2014. Xue P, Crum CM, Thibodeau PH
Regulation of ABCC6 trafficking and stability by a conserved C-terminal PDZ-like sequence.
PLoS One. 2014 May 19;9(5):e97360. doi: 10.1371/journal.pone.0097360. eCollection 2014., [PMID:24840500]

Abstract [show]
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.

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Sentences [show]
No. Sentence Comment
115 To further confirm these species were the result of changes in glycosylation, the single glycosylation site was mutated (N15D) and expressed. Login to comment
117 Migration of the single N15D protein band was consistent with the fully deglycosylated protein, band A, in the wildtype ABCC6 expressing cells. Deletion of the six C-terminal amino acids (D6-COOH), which includes the complete PDZ ligands found in other ABCC family members, showed dramatic changes in both protein biosynthesis and protein trafficking as measured by western blotting (Figure 1C, D). Login to comment
135 No observable changes in immunofluorescence were seen between the wildtype and N15D glycosylation mutant (data not shown). Login to comment
195 The N15D substitution blocks N-linked glycosylation and is a reference for the unglycosylated wildtype and D6-COOH proteins. Login to comment