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Modeling

Molecular Dynamics and Mutational Analysis of a Channelopathy mutation in the IIS6 Helix of Ca_V1.2

Anna Stary, Michaela Kudrnac, Stanislav Beyl, Annette Hohaus, Eugen Timin, Peter Wolschann, H. Robert Guy and Steffen Hering

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A channelopathy mutation in segment IIS6 of Ca_V1.4 (I745T) has been shown to cause severe visual impairment by shifting the activation and inactivation curves to more hyperpolarised voltages and slowing activation and inactivation kinetics. A similar gating phenotype is caused by the corresponding mutation, I781T, in Ca_V1.2 (midpoint of activation curve (V_0.5) shifted to -37.7 ± 1.2 mV). We show here that wild type gating can partially be restored by a helix stabilising rescue mutation N785A. V0.5 of I781T/N785A (V_0.5 = -21.5 ± 0.6 mV) was shifted back towards wild type (V_0.5 = -9.9±1.1 mV). Homology models developed in our group (see accompanying article for details) were used to perform MD-simulations on wild-type and mutant channels. Systematic changes in segment IIIS6 (M1187 - F1194) and in helix IIS6 (N785-L786) were observed. The simulated structural changes in S6 segments of I781T/N785A were less pronounced than in I781T. A delicate balance between helix flexibility and stability enabling the formation of hydrophobic seals at the inner channel mouth appears to be important for wild type Ca_V1.2 gating. Our study illustrates that effects of mutations in the lower part of IIS6 may not be localized to the residue or even segment being mutated, but may affect conformations of interacting segments.

Authors

Anna Stary

Max Planck Institute for Biophysical Chemistry

Michaela Kudrnac

Universtiy of Vienna

Stanislav Beyl

University of Vienna

Annette Hohaus

University of Vienna

Eugen Timin

University of Vienna

Peter Wolschann

Institute for Theoretical Chemistry

H. Robert Guy

NIH

Steffen Hering

University of Vienna

This is an open-access article

 Download PDF

If the document does not open, please right-click on the link (control-click on a Macintosh) and select the option to save the file to disk.