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Biochem Biophys Res Commun. 2009 Feb 13;379(3):706-9. doi: 10.1016/j.bbrc.2008.12.142. Epub 2009 Jan 6.

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

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Institute of Enzymology, Hungarian Academy of Sciences, Karolina ut 29, Budapest, Hungary.


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.

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