Allosteric Regulation of Rod Photoreceptor Phosphodiesterase 6 (PDE6) Elucidated by Chemical Cross-Linking and Quantitative Mass Spectrometry

Journal of Molecular Biology
Feixia ChuRick H Cote

Abstract

Photoreceptor phosphodiesterase (PDE6) is the central effector enzyme in the visual excitation pathway in rod and cone photoreceptors. Its tight regulation is essential for the speed, sensitivity, recovery, and adaptation of visual signaling. The rod PDE6 holoenzyme (Pαβγ2) is composed of a catalytic heterodimer (Pαβ) that binds two inhibitory γ subunits. Each of the two catalytic subunits (Pα and Pβ) contains a catalytic domain responsible for cGMP hydrolysis and two tandem GAF domains, one of which binds cGMP noncatalytically. Unlike related GAF-containing PDEs where cGMP binding allosterically activates catalysis, the physiological significance of cGMP binding to the GAF domains of PDE6 is unknown. To elucidate the structural determinants of PDE6 allosteric regulators, we biochemically characterized PDE6 complexes in various allosteric states (Pαβ, Pαβ-cGMP, Pαβγ2, and Pαβγ2-cGMP) with a quantitative cross-linking/mass spectrometry approach. We employed a normalization strategy to dissect the cross-linking reactivity of individual residues in order to assess the spatial cross-linking propensity of detected pairs. In addition to identifying cross-linked pairs that undergo conformational changes upon ligand binding, we observe...Continue Reading

References

Jun 1, 1982·Proceedings of the National Academy of Sciences of the United States of America·A YamazakiM W Bitensky
May 24, 1994·Proceedings of the National Academy of Sciences of the United States of America·R H CoteV Y Arshavsky
Dec 5, 1993·Journal of Molecular Biology·A Sali, T L Blundell
May 2, 1997·The Journal of Biological Chemistry·A E GranovskyN O Artemyev
Jul 21, 2004·Molecular Cell·Kam Y J ZhangGideon Bollag
Jul 21, 2004·Journal of Computational Chemistry·Eric F PettersenThomas E Ferrin
Nov 18, 2004·Proceedings of the National Academy of Sciences of the United States of America·Feixia ChuAlma L Burlingame
Jun 1, 2006·The Journal of Biological Chemistry·Huanchen WangHengming Ke
Feb 20, 2007·Current Topics in Medicinal Chemistry·Hengming Ke, Huanchen Wang
Jan 19, 2008·Analytical Chemistry·Xin GuoBradford W Gibson
Jan 31, 2008·Proceedings of the National Academy of Sciences of the United States of America·Jikui SongJohn L Markley
May 6, 2008·Vision Research·Theodore G Wensel
Oct 8, 2009·Molecular & Cellular Proteomics : MCP·Feixia ChuRobert J Chalkley
Oct 16, 2009·Proceedings of the National Academy of Sciences of the United States of America·Jayvardhan PanditFrank S Menniti
Apr 20, 2010·Biochemistry·Zhongming Zhang, Nikolai O Artemyev
Sep 24, 2010·The Journal of Biological Chemistry·Huanchen WangHengming Ke
Apr 30, 2011·Physiological Reviews·Sharron H FrancisJackie D Corbin
Nov 15, 2011·The Journal of Biological Chemistry·Vadim Y Arshavsky, Marie E Burns
May 21, 2013·Annual Review of Neuroscience·Krzysztof Palczewski, Tivadar Orban
Dec 18, 2013·Molecular & Cellular Proteomics : MCP·Michael J TrnkaRobert J Chalkley
Apr 15, 2014·Journal of Molecular Biology·Timothy O StreetDavid A Agard
Jul 15, 2015·The Journal of Biological Chemistry·Zhixian ZhangMelina A Agosto
Jun 2, 2018·Methods : a Companion to Methods in Enzymology·Feixia ChuHieu T Nguyen
Jun 19, 2019·Proceedings of the National Academy of Sciences of the United States of America·Faisa OmarDavid J P Henderson
Feb 1, 2014·Molecular & Cellular Proteomics : MCP·Michael J TrnkaRobert J Chalkley

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Citations

May 5, 2021·Current Opinion in Structural Biology·Sahil Gulati, Krzysztof Palczewski

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