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Abstract
In 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.
Highlights
Retinitis pigmentosa (RP) is a progressive retinal degenerative disease caused by a heterogeneous genetic defects that affect more than a million people worldwide
Our analyses suggest that the principal source of the functional differences is attributed to mutation-induced structural changes that lead to a ruptured disulfide bond (Cys110– Cys187) in the extracellular domain (ECD) and the consequent misfolding around the retinal-binding site that alters the stability of the Schiff base linkage - and the pathway to activation
The formation of the intracellular protein aggregates is principal to disease pathogenesis and postulates a direct mechanism for the progression of photoreceptor degradation. The results from this investigation indicate that the P23H mutation in rhodopsin represents a cellular-level allosteric perturbation
Summary
Retinitis pigmentosa (RP) is a progressive retinal degenerative disease caused by a heterogeneous genetic defects that affect more than a million people worldwide. The escaped P23H forms aggregates that create abnormal internal membrane structures that are destructive to WT receptors In this revised interpretation, it is the toxicity to WT receptors and the gain of function attributes of P23H in the ROS that lead to photoreceptor cell degeneration. Irrespective of the specific mechanism underlying the progression of RP, it has become increasingly more apparent that the conformational plasticity[4,8] of P23H is a major contributing factor to the underlying causation of disease. For this reason, in this investigation, we use both THz spectroscopy and MD simulation to characterize the molecular-level functional dynamics and conformational heterogeneity of P23H rhodopsin. Our aim is to gain greater insight into the connection that links the inherent propensity of P23H to adopt a more conformationally flexible structure and the consequent shift in protein interaction dynamics that leads to the disease state
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