Clustering of disease-causing mutations on the domain–domain interfaces of ABCC6

Fülöp, Krisztina; Barna, L; Symmons, Orsolya; Závodszky, Pé ter; Váradi, András

doi:10.1016/j.bbrc.2008.12.142

Cited by 38 publications

(40 citation statements)

References 24 publications

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“…[34] Three transmembrane domains and two cytosolic, nucleotide-binding domains are encoded by a single polypeptide and putatively form the functional unit for transport. The two core transmembrane domains (TMD1 and TMD2) putatively provide the channel for substrate movement across the membrane.…”

Section: Resultsmentioning

confidence: 99%

Regulation of ABCC6 Trafficking and Stability by a Conserved C-terminal PDZ-Like Sequence

2014

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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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Section: Resultsmentioning

confidence: 99%

Regulation of ABCC6 Trafficking and Stability by a Conserved C-terminal PDZ-Like Sequence

2014

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“…Moreover, we expect this theme could be relevant to many human diseases, given the preponderance of multi-domain proteins in the proteomes of higher organisms [30]. Several other proteins involved in inherited disorders also have missense variants that localize to interdomain interfaces [31–33], although their distribution across the 3D-structure is much wider overall, perhaps due to the larger number of mutations identified.…”

Section: Discussionmentioning

confidence: 99%

Induced Structural Disorder as a Molecular Mechanism for Enzyme Dysfunction in Phosphoglucomutase 1 Deficiency

Stiers

Kain

Graham

et al. 2016

Journal of Molecular Biology

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Human phosphoglucomutase 1 (PGM1) plays a central role in cellular glucose homeostasis, mediating the switch between glycolysis and gluconeogenesis through the conversion of glucose 1-phosphate and glucose 6-phosphate. Recent clinical studies have identified mutations in this enzyme as the cause of PGM1 deficiency, an inborn error of metabolism classified as both a glycogen storage disease and a congenital disorder of glycosylation. Reported here are the first crystal structures of two disease-related missense variants of PGM1, along with the structure of the wild-type enzyme. Two independent glycine to arginine substitutions (G121R and G291R), both affecting key active site loops of PGM1, are found to induce regions of structural disorder, as evidenced by a nearly complete loss of electron density for as many as 23 amino acids. The disordered regions are not contiguous in sequence to the site of mutation, and even cross domain boundaries. Other structural rearrangements include changes in the conformations of loops and side chains, some of which occur nearly 20 Å away from the site of mutation. The induced structural disorder is correlated with increased sensitivity to proteolysis and lower resolution diffraction, particularly for the G291R variant. Examination of the multi-domain effects of these G→R mutations establishes a correlation between interdomain interfaces of the enzyme and missense variants of PGM1 associated with disease. These crystal structures provide the first insights into the structural basis of enzyme dysfunction in PGM1 deficiency, and highlight a growing role for biophysical characterization of proteins in the field of precision medicine.

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“…The introduction of mutations at the interface of TMD-NBD severely disrupts the biogenesis the complex (15). Similarly, the folding and trafficking of other ABC transporters such as CFTR (cystic fibrosis transmembrane conductance regulator) and ABCC6 is particularly sensitive to mutations in this region (24,25). The study of the MalFGK 2 variants as those isolated in this work may help to understand why this interface …”

Section: Discussionmentioning

confidence: 99%

Nucleotide-free MalK Drives the Transition of the Maltose Transporter to the Inward-facing Conformation

Bao

Duong

2014

Journal of Biological Chemistry

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Clustering of disease-causing mutations on the domain–domain interfaces of ABCC6

Cited by 38 publications

References 24 publications

Regulation of ABCC6 Trafficking and Stability by a Conserved C-terminal PDZ-Like Sequence

Regulation of ABCC6 Trafficking and Stability by a Conserved C-terminal PDZ-Like Sequence

Induced Structural Disorder as a Molecular Mechanism for Enzyme Dysfunction in Phosphoglucomutase 1 Deficiency

Nucleotide-free MalK Drives the Transition of the Maltose Transporter to the Inward-facing Conformation

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