Conformational perturbation, allosteric modulation of cellular signaling pathways, and disease in P23H rhodopsin

Abstract

AbstractIn this investigation we use THz spectroscopy and MD simulation to study the functional dynamics and conformational stability of P23H rhodopsin. The P23H mutation of rod opsin is the most common cause of human binding autosomal dominant retinitis pigmentosa (ADRP), but the precise mechanism by which this mutation leads to photoreceptor cell degeneration has not yet been elucidated. Our measurements confirm conformational instability in the global modes of the receptor and an active-state that uncouples the torsional dynamics of the retinal with protein functional modes, indicating inefficient signaling in P23H and a drastically altered mechanism of activation when contrasted with the wild-type receptor. Further, our MD simulations indicate that P23H rhodopsin is not functional as a monomer but rather, due to the instability of the mutant receptor, preferentially adopts a specific homodimerization motif. The preferred homodimer configuration induces structural changes in the receptor tertiary structure that reduces the affinity of the receptor for the retinal and significantly modifies the interactions of the Meta-II signaling state. We conjecture that the formation of the specific dimerization motif of P23H rhodopsin represents a cellular-wide signaling perturbation that is directly tied with the mechanism of P23H disease pathogenesis. Our results also support a direct role for rhodopsin P23H dimerization in photoreceptor rod death.