Towards a Structural Understanding of Cantú Disease Associated Gating Perturbations in the KATP Potassium Channel

Abstract

Cantu syndrome is a rare disease affecting a small number of people worldwide. It is characterized by multiple symptoms including distinctive facial features, cardiac abnormalities, hypertrichosis and lymphedema. This genetic disorder is caused by dominant gain-of-function mutations in the ATP-dependent potassium channel KATP impeding channel closure at the correct ATP concentration. These channels consist of a sulfonylurea transporter subunit (encoded by the ABCC9 gene), and the pore-forming KIR6.1 subunit (encoded by the KCNJ8 gene).To obtain insights into the structure of this large protein complex, homology modeling techniques are applied. For the KIR6.1 subunit we used the crystal structure of KIR3.2 as template (pdb-code 3SYA; ∼50% sequence identity). The sulfonyl urea transporter subunit was modeled on the distantly related TM287/288 ATP binding cassette transporter (pdb-code 4Q4H; ∼25% sequence identity).These models are currently used to establish the structural basis of known Cantu associated mutants. Two known gain-of function mutations (V65M and C176S) are located in the pore module of the KATP channel. Both amino acids are in close contact in the closed channel state. During channel opening, this region undergoes large conformational changes, including rearrangements of these two amino acids. To further investigate how perturbations in this area influence gating, we are currently performing molecular dynamics simulations.From these studies, a better understanding of Cantu disease and the function of the KATP channel in general (a well-known pharmaceutical target for treatment of diabetes mellitus) are expected.