Intrinsically disordered γ-subunit of cGMP phosphodiesterase encodes functionally relevant transient secondary and tertiary structure

The retinal phosphodiesterase (PDE6) inhibitory gamma-subunit (PDE gamma) plays a central role in vertebrate phototransduction through alternate interactions with the catalytic alpha beta-subunits of PDE6 and the a-subunit of transducin (at). Detailed structural analysis of PDE gamma has been hampered by its intrinsic disorder. We present here the NMR solution structure of PDE gamma, which reveals a loose fold with transient structural features resembling those seen previously in the x-ray structure of PDE gamma(46-87) when bound to at in the transition-state complex. NMR mapping of the interaction between PDE gamma(46-87) and the chimeric PDE5/6 catalytic domain confirmed that C-terminal residues 74-87 of PDE gamma are involved in the association and demonstrated that its W70 indole group, which is critical for subsequent binding to at, is left free at this stage. These results indicate that the interaction between PDE gamma and at during the phototransduction cascade involves the selection of preconfigured transient conformations.