The Retinal cGMP Phosphodiesterase γ-Subunit — A Chameleon

Abstract

Intrinsically disordered proteins (IDPs) represent an emerging class of proteins (or domains) that are characterized by a lack of ordered secondary and tertiary structure. This group of proteins has recently attracted tremendous interest primarily because of a unique feature: they can bind to different targets due to their structural plasticity, and thus fulfill diverse functions. The inhibitory γ-subunit (PDEγ) of retinal PDE6 is an intriguing IDP, of which unique protein properties are being uncovered. PDEγ critically regulates the turn on as well as the turn off of visual signaling through alternate interactions with the PDE6 catalytic core, transducin, and the regulator of G protein signaling RGS9-1. The intrinsic disorder of PDEγ does not compromise, but rather, optimizes its functionality. PDEγ “curls up” when free in solution but “stretches out” when binding with the PDE6 catalytic core. Conformational changes of PDEγ also likely occur in its C-terminal PDE6-binding region upon interacting with transducin during PDE6 activation. Growing evidence shows that PDEγ is also a player in non-phototransduction pathways, suggesting additional protein targets. Thus, PDEγ is highly likely to be adaptive in its structure and function, hence a “chameleon”.

Characterization of Conformational Changes and Protein-Protein Interactions of Rod Photoreceptor Phosphodiesterase (PDE6)

“…Our analysis of the hydrodynamic behavior of P␥ in aqueous solution using AU-FDS agrees well with structural data using other methods (38,40) and lends support to the conclusion that P␥ is a disordered, extended structure in solution and binds at multiple sites along the surface of the PDE6 catalytic dimer (consistent with chemical cross-linking studies, reviewed in Ref 40). The observation that binding of P␥ to P␣␤ occurs without a significant change in overall shape of the resulting heterotetramer (Fig.…”

“…Biochemical evidence indicates that the N-terminal portion of P␥ interacts with the GAFa domain of the catalytic subunits, whereas the C-terminal portion of P␥ interacts with the catalytic domains of P␣␤ (40). To test the hypothesis that binding of P␥ to P␣␤ might induce a structural change in conformation of the domain organization of PDE6, we examined the effects of mixing P␥ with P␣␤ prior to determining the hydrodynamic properties of the reconstituted holoenzyme.…”

“…7A) supports the idea that P␥ conforms to the overall shape of the catalytic dimer upon binding ( Table 1). The function of these multiple sites of interactions between the extended, partially unfolded structure of P␥ and the highly organized three-domain structure of the PDE6 catalytic subunits remains a subject of inquiry and is probably fundamental to the multiple roles P␥ plays in visual excitation and recovery (40).…”

Functional Mapping of Interacting Regions of the Photoreceptor Phosphodiesterase (PDE6) γ-Subunit with PDE6 Catalytic Dimer, Transducin, and Regulator of G-protein Signaling9–1 (RGS9–1)

“…The 87-amino acid P␥ subunit (localized to the signal-transducing outer segment compartment of rod photoreceptors) is remarkable for the variety of regulatory functions it performs as well as the multitude of proteins with which it interacts in addition to the catalytic subunits of PDE6 (6). The primary regulatory role of P␥ is to regulate access of substrate to the catalytic pocket of PDE6 and thereby control cGMP hydrolytic rates.…”

N-terminal Half of the cGMP Phosphodiesterase γ-Subunit Contributes to Stabilization of the GTPase-accelerating Protein Complex

“…[1][2][3][4]. The signaling is turned on when the GTP-bound ␣-subunit of transducin (␣t), which is converted from the GDP-bound conformation by light-excited rhodopsin, activates PDE6 by interacting with PDE␥ and displacing its C terminus from the PDE6 catalytic pocket (signaling state).…”