title: Clustering of disease-causing mutations on the domain-domain interfaces of ABCC6.
abstract: Mutations in ABCC6 are responsible for pseudoxanthoma elasticum (PXE), a rare genetic disease affecting the elastic tissues of the body. ABCC6 encodes a 1503 amino acid long ABC transporter, ABCC6/MRP6. The functional link between the impaired activity of the protein and the disease is not known. We have built a homology model of this transporter, and analyzed the distribution of the known 119 missense PXE-associated mutations within the predicted structure. Significant clustering of the missense mutations has been found at complex domain-domain interfaces: at the transmission interface that involves four intracellular loops and the two ABC domains as well as at the ABC-ABC interacting surfaces. The mutations affecting these regions are 2.75 and 3.53-fold more frequent than the average mutational rate along the transporter protein sequence. These data provide a genetic proof of the importance of these domain-domain interactions in the ABCC6 transporter.
authors.affiliation: Institute of Enzymology, Hungarian Academy of Sciences, Karolina ut 29, Budapest, Hungary.
authors.forename: Krisztina
authors.initials: K
authors.lastname: Fülöp
authors.forename: László
authors.initials: L
authors.lastname: Barna
authors.forename: Orsolya
authors.initials: O
authors.lastname: Symmons
authors.forename: Péter
authors.initials: P
authors.lastname: Závodszky
authors.forename: András
authors.initials: A
authors.lastname: Váradi
mesh_terms: D002462:Cell Membrane / Q000737:chemistry / Q000378:metabolism; D016000:Cluster Analysis; D006801:Humans; D008956:Models, Chemical; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D020125:Mutation, Missense; D017434:Protein Structure, Tertiary / Q000235:genetics; D011561:Pseudoxanthoma Elasticum / Q000235:genetics*; D017385:Sequence Homology
chemical_list: D027425:ATP-Binding Cassette, Sub-Family C Proteins; C102029:ABCC6 protein, human