49* Probing the oligomeric state of CFTR

Abstract

Models of the 3D structure of full-length human CFTR described during the last years have provided new insights into the molecular basis of CFTR functioning. They have in particular shed light on the interdomain interfaces which are critical for signal transmission and can thus be considered for in silico screening of drugs (correctors and modulators) capable of filling the cavities displayed at these interfaces in the wild type or mutated protein. However, the modeling methodology does largely influence the characteristics of those interdomain interfaces. Here, relying on all the available experimental data on ABC transporters (full length and isolated domains), we show that there is a considerable structural plasticity in these regions which allows to adapt the partner domains. The careful consideration of such a structural plasticity in our modeling strategy leads us to propose at present four models of human CFTR, two (based on the Sav1866 and MsbA structures) in a similar open channel conformation and two (based on the MsbA and P-gp structures) in notably different closed channel conformations. We interestingly show that the global features of the transmission interfaces [between the membrane-spanning domains (MSDs) and the nucleotide binding domains (NBDs)] are remarkably conserved in these models between the open and closed forms. Further investigation of the details of the MSDs/NBDs interface also suggests that subtle differences may participate in the general mechanisms by which the signal is transmitted between MSDs and NBDs. Supported by the association Vaincre La Mucoviscidose, Paris, France.