Abstract:
This research probes the role of Ca2+ and CABP4 in rod photoreceptors for visual signaling,
particularly in varying light conditions. In illuminated situations, rhodopsin activation and closure
of the presynaptic Cav1.4 channel are associated with normal visual signaling. However, under
low light condition, prolonged opening of the ion channels results in elevated levels of Ca2+ and
calcium-binding proteins specifically CABP4, which prominently regulate Cav1.4 to enhance
visual processing efficiency. Mutations in CABP4 have been associated with various diseases,
including night blindness, rod-cone dystrophy, and myopia. Thus, to probe the regulation
mechanistics of CABP4 and its role in night blindness, Biological Regulatory Network (BRN) has
been constructed and simulated. Simulation results of final BRN revealed the model's sensitivity
to changes in both CABP4 and Ca2+ concentration levels and thus, advocate CABP4 along with
Ca2+ modulator as a potential therapeutic option against night blindness.
Furthermore, the regulation of Cav1.4 by CABP4 under both normal and mutated
conditions have been simulated. Due to the unavailability of a PDB structure, different homology
models of CABP4 have been developed and evaluated. Furthermore, molecular docking and
simulations studies were performed to identify favorable binding hypothesis of mutant and wild
type CABP4. Our findings indicate that specific residues such as Leu257, Asn258, Thr262,
Asp264, Asp266, Ser273, and His275 of CABP4 are essential for binding with the IQ motif. While
Mutant-CABP4 was failed to interact properly with IQ motif, which might lead to night blindness.
Both complexes were validated with MD simulation; the Wild-type CABP4-IQ complex remained
stable at RMSD ranging from 0.4 to 0.5 Å, while the Mutant CABP4-IQ complex showed
fluctuating RMSD ranging from 0.2 to 0.8 Å. Residue fluctuations and hydrogen bond analysis
highlighted the residues required for interaction of IQ domain with CABP4 for functional rod
photoreceptors. Finally, our protocol revealed the role of CABP4 and Ca2+ in night blindness
which could pave the way towards therapeutic intervention against the night blindness.
