Molecular Modeling of the Structural and Dynamical Changes in Calcium Channel TRPV5 Induced by the African-Specific A563T Variation

Transient receptor potential cation
channels, vanilloid subfamily,
member 5 (TRPV5) plays a key role in active Ca2+ reabsorption
in the kidney. Variations in TRPV5 occur at high frequency in African
populations and may contribute to their higher efficiency of Ca2+ reabsorption. One of the African specific variations, A563T,
exhibits increased Ca2+ transport ability. However, it
is unclear how this variation influences the channel pore. On the
basis of the structure of TRPV1, a TRPV5 model was generated to simulate
the structural and dynamical changes induced by the A563T variation.
On the basis of this model, amino acid residue 563 interacts with
V540, which is one residue away from the key residue, D542, involved
in Ca2+ selectivity and Mg2+ blockade. The A563T
variation increases secondary structure stability and reduces dynamical
motion of D542. In addition, the A563T variation alters the electrostatic
potential of the outer surface of the pore. Differences in contact
between selective filter residues and residue 563 and in electrostatic
potential between the two TRPV5 variants were also observed in another
model derived from an alternative alignment in the selective filters
between TRPV5 and TRPV1. These findings indicate that the A563T variation
induces structural, dynamical, and electrostatic changes in the TRPV5
pore, providing structural insight into the functional alterations
associated with the A563T variation.