Determinants for phosphodiesterase 6 inhibition by its gamma-subunit

Zhongming Zhang; Nikolai O Artemyev

doi:10.1021/bi100354a

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Determinants for phosphodiesterase 6 inhibition by its gamma-subunit

Journal article

Peer reviewed

Determinants for phosphodiesterase 6 inhibition by its gamma-subunit

Zhongming Zhang and Nikolai O Artemyev

Biochemistry (Easton), Vol.49(18), pp.3862-3867

05/11/2010

DOI: 10.1021/bi100354a

PMCID: PMC2864356

PMID: 20397626

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Abstract

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.

Amino Acid Sequence

Catalytic Domain

Cyclic Nucleotide Phosphodiesterases, Type 6 - metabolism

Protein Structure, Secondary

Down-Regulation

Humans

Molecular Conformation

Molecular Sequence Data

Cyclic Nucleotide Phosphodiesterases, Type 6 - chemistry

Cyclic Nucleotide Phosphodiesterases, Type 6 - genetics

Protein Subunits - metabolism

Sequence Alignment

Cyclic GMP - chemistry

Protein Subunits - chemistry

Protein Subunits - genetics

Details

Title: Subtitle: Determinants for phosphodiesterase 6 inhibition by its gamma-subunit
Creators: Zhongming Zhang - Department of Molecular Physiology and Biophysics, University of Iowa Carver College of Medicine, Iowa City, Iowa 52242, USA
Nikolai O Artemyev
Resource Type: Journal article
Publication Details: Biochemistry (Easton), Vol.49(18), pp.3862-3867
DOI: 10.1021/bi100354a
PMID: 20397626
PMCID: PMC2864356
NLM abbreviation: Biochemistry
ISSN: 0006-2960
eISSN: 1520-4995
Publisher: United States
Grant note: R01 EY010843 / NEI NIH HHS R01 EY010843-17 / NEI NIH HHS EY-10843 / NEI NIH HHS
Language: English
Date published: 05/11/2010
Academic Unit: Molecular Physiology and Biophysics; Iowa Neuroscience Institute; Ophthalmology and Visual Sciences
Record Identifier: 9984025442702771

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