Determinants for phosphodiesterase 6 inhibition by its gamma-subunit.
The interaction of phosphodiesterase 6 (PDE6) with its inhibitory Pgamma-subunits (Pgamma) is unparalleled among PDE families and is central to vertebrate phototransduction. The C-terminus of Pgamma occludes the active site of PDE6, thereby preventing hydrolysis of cGMP. In this study, we examine the determinants of this critical interaction using structure-based loss-of-function mutagenesis of a chimeric PDE5/PDE6 catalytic domain and gain-of-function mutagenesis of the PDE5 catalytic domain. This analysis revealed the key role of PDE6-specific residues within the catalytic domain M-loop-alpha-helix 15 region and suggested an important contribution of the H-loop-M-loop interface to the PDE6 inhibition by the Pgamma C-terminus. Identification of the determinants for the PDE6-Pgamma interaction offers insights into the evolution of the visual effector enzyme.
Zhang
Zhongming
Z
Department of Molecular Physiology and Biophysics, University of Iowa Carver College of Medicine, Iowa City, Iowa 52242, USA.
Artemyev
Nikolai O
NO
D000595:Amino Acid Sequence; D020134:Catalytic Domain; D006152:Cyclic GMP / Q000737:chemistry; D054707:Cyclic Nucleotide Phosphodiesterases, Type 6 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation; D006801:Humans; D008968:Molecular Conformation; D008969:Molecular Sequence Data; D017433:Protein Structure, Secondary; D021122:Protein Subunits / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D016415:Sequence Alignment
D021122:Protein Subunits; D054707:Cyclic Nucleotide Phosphodiesterases, Type 6; D006152:Cyclic GMP
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