ABCMdb: A database for the comparative analysis of protein mutations in ABC transporters, and a potential framework for a general application

Gyimesi, Gergely; Borsodi, Dávid; Sarankó, Hajnalka; Tordai, Hedvig; Sarkadi, Balázs; Hegedüs, Tamás

doi:10.1002/humu.22138

Cited by 29 publications

(19 citation statements)

References 45 publications

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“…4). As G755R equivalent mutations are associated with multiple ABC-transporter diseases, these data suggest that this substitution may generally result in altered protein function and not biosynthesis, consistent with measurements of multiple LSGGQ mutants in CFTR (40,47). This result, along with those of G551D and G1349D in CFTR also argue against a requirement for the formation of the NBD heterodimer in normal protein biosynthesis.…”

Section: Domain Scaffolding Rescues Abcc6 Biosynthesissupporting

confidence: 68%

“…Structural analyses of these NBD homo-and heterodimers indicate that the Walker A and B sequence from one NBD are juxtaposed with the LSGGQ signature sequence of the opposing protomer. Analysis of the ABC transporter mutation database revealed a disease-causing mutation, G755R, which is located within the LSGGQ signature sequence of NBD1 and is identified in multiple ABC transporterrelated diseases (40). Structural modeling using ATP-bound NBD dimers as a template for the ABCC6 NBDs demonstrates the G755R mutation would putatively block NBD dimerization by introducing steric and electrostatic clashes with the ATP bound at the NBD2 composite site (Fig.…”

Section: Journal Of Biological Chemistry 1563mentioning

confidence: 99%

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Stabilization of Nucleotide Binding Domain Dimers Rescues ABCC6 Mutants Associated with Pseudoxanthoma Elasticum

Ran

Thibodeau

2017

Journal of Biological Chemistry

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Edited by Norma AllewellABC transporters are polytopic membrane proteins that utilize ATP binding and hydrolysis to facilitate transport across biological membranes. Forty-eight human ABC transporters have been identified in the genome, and the majority of these are linked to heritable disease. Mutations in the ABCC6 (ATP binding cassette transporter C6) ABC transporter are associated with pseudoxanthoma elasticum, a disease of altered elastic properties in multiple tissues. Although ϳ200 mutations have been identified in pseudoxanthoma elasticum patients, the underlying structural defects associated with the majority of these are poorly understood. To evaluate the structural consequences of these missense mutations, a combination of biophysical and cell biological approaches were applied to evaluate the local and global folding and assembly of the ABCC6 protein. Pseudoxanthoma elasticum (PXE)2 is a multisystem autosomal recessive disease that results in the dystrophic mineralization of elastic tissues putatively due to the loss of one or more circulatory factors (1, 2). The mineralization and subsequent degradation of elastic fibers impacts multiple organs, including the vasculature, eyes, skin, and gastrointestinal tract (3). Patients suffer from premature arteriosclerosis, reduced peripheral circulation, loss of central vision, loss of skin tone, and bleeding in the digestive tract (4). Recent work suggests that a loss of circulating pyrophosphates, resulting from altered nucleotide secretion and conversion by nucleotide pyrophosphatases in the circulatory system, is associated with ectopic mineralization (5, 6). At present, only symptomatic treatments exist for PXE (4, 7).PXE is caused by mutations in the ATP-binding cassette transporter C6 (ABCC6), a member of the multidrug resistant group of ABC proteins (1, 8 -10). ABC transporters are active transporters that couple the energy of ATP hydrolysis to the directional transport of solutes (11). Although multiple putative substrates have been identified for ABCC6, the PXE-specific solute(s) and the mechanisms of ABCC6 functional regulation have not been fully elucidated (5, 9, 12). ABCC6 is composed of five domains: three transmembrane domains (TMD0/1/2) and two cytosolic nucleotide binding domains (NBD1/2) (13, 14). The core TMDs (TMD1/2) facilitate solute movement across the membrane, whereas the NBDs provide the energy for transport through nucleotide binding and hydrolysis. The NBDs heterodimerize in response to binding two ATP molecules within the conserved domain-domain interface. This dimerization induces conformational changes in the NBDs that propagate through the TMDs (15-17). ATP hydrolysis putatively reverses these conformational changes, thereby promoting transport cycling and multiple rounds of solute efflux. The NBDs are physically coupled to the TMDs through extensions of the TMD helices and intracellular loops, and these interactions are disrupted in multiple ABC transporter disease states (17-20). It is not known how the N-terminal TMD (TMD0...

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Section: Domain Scaffolding Rescues Abcc6 Biosynthesissupporting

confidence: 68%

Section: Journal Of Biological Chemistry 1563mentioning

confidence: 99%

Stabilization of Nucleotide Binding Domain Dimers Rescues ABCC6 Mutants Associated with Pseudoxanthoma Elasticum

Ran

Thibodeau

2017

Journal of Biological Chemistry

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“…An up-to-date database summarizes the available information on the mutant variants of ABC transporters including BSEP (see http://abcmutations.hegelab.org/) [54]. All regions of BSEP can be affected, but the hot spots for mutations are the NBDs and the cytoplasmic loops.…”

Section: Human Diseases Associated With Bsep Mutationsmentioning

confidence: 99%

Recent advances in the exploration of the bile salt export pump (BSEP/ABCB11) function

Telbisz

Homolya

2015

Expert Opinion on Therapeutic Targets

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IntroductionThe bile salt export pump (BSEP/ABCB11), residing in the apical membrane of hepatocyte, mediates the secretion of bile salts into the bile. A range of human diseases is associated with the malfunction of BSEP, including fatal hereditary liver disorders and mild cholestatic conditions. Manifestation of these diseases primarily depends on the mutation type; however, other factors such as hormonal changes and drug interactions can also trigger or influence the related diseases. Areas coveredHere, we summarize the recent knowledge on BSEP by covering its transport properties, cellular localization, regulation, and major mutations/polymorphisms, as well as the hereditary and acquired diseases associated with BSEP dysfunction. We discuss the different model expression systems employed to understand the function of the BSEP variants, their drug interactions, and the contemporary therapeutic interventions. Expert opinionThe limitations of the available model expression systems for BSEP result in controversial conclusions, and obstruct our deeper insight into BSEP deficiencies and BSEPrelated drug interactions. The knowledge originating from different methodologies, such as clinical studies, molecular genetics, as well as in vitro and in silico modeling, should be integrated and harmonized. Increasing availability of robust molecular biological tools and our better understanding of the mechanism of BSEP deficiencies should make the personalized, mutation-based therapeutic interventions more attainable.

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“…As well as those cited above, a further example would be the G-protein Coupled Receptors (GPCRs) where the so-called Ballesteros and Weinstein numbering scheme [23] is commonly used rather than the position in the full length of mature sequences. Thus, one must temper user expectations of what is possible within text mining and in some cases it may well be more desirable to use an “entity-specific” method such as those created for ABC transporters [24] and Fabry disease [25].…”

Section: Resultsmentioning

confidence: 99%

Mutationmapper: A Tool to Aid the Mapping of Protein Mutation Data

Vohra

Biggin

2013

PLoS ONE

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There has been a rapid increase in the amount of mutational data due to, amongst other things, an increase in single nucleotide polymorphism (SNP) data and the use of site-directed mutagenesis as a tool to help dissect out functional properties of proteins. Many manually curated databases have been developed to index point mutations but they are not sustainable with the ever-increasing volume of scientific literature. There have been considerable efforts in the automatic extraction of mutation specific information from raw text involving use of various text-mining approaches. However, one of the key problems is to link these mutations with its associated protein and to present this data in such a way that researchers can immediately contextualize it within a structurally related family of proteins. To aid this process, we have developed an application called MutationMapper. Point mutations are extracted from abstracts and are validated against protein sequences in Uniprot as far as possible. Our methodology differs in a fundamental way from the usual text-mining approach. Rather than start with abstracts, we start with protein sequences, which facilitates greatly the process of validating a potential point mutation identified in an abstract. The results are displayed as mutations mapped on to the protein sequence or a multiple sequence alignment. The latter enables one to readily pick up mutations performed at equivalent positions in related proteins. We demonstrate the use of MutationMapper against several examples including a single sequence and multiple sequence alignments. The application is available as a web-service at http://mutationmapper.bioch.ox.ac.uk.

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ABCMdb: A database for the comparative analysis of protein mutations in ABC transporters, and a potential framework for a general application

Cited by 29 publications

References 45 publications

Stabilization of Nucleotide Binding Domain Dimers Rescues ABCC6 Mutants Associated with Pseudoxanthoma Elasticum

Stabilization of Nucleotide Binding Domain Dimers Rescues ABCC6 Mutants Associated with Pseudoxanthoma Elasticum

Recent advances in the exploration of the bile salt export pump (BSEP/ABCB11) function

Mutationmapper: A Tool to Aid the Mapping of Protein Mutation Data

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