Molecular architecture of photoreceptor phosphodiesterase elucidated by chemical cross-linking and integrative modeling

Xiaohui Zeng-Elmore, Xiong Zhuo Gao, Riccardo Pellarin, Dina Schneidman-Duhovny, Xiu Jun Zhang, Katie A. Kozacka, Yang Tang, Andrej Sali, Robert J. Chalkley, Rick H. Cote, Feixia Chu*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

33 Scopus citations

Abstract

Photoreceptor phosphodiesterase (PDE6) is the central effector enzyme in visual excitation pathway in rod and cone photoreceptors. Its tight regulation is essential for the speed, sensitivity, recovery and adaptation of visual detection. Although major steps in the PDE6 activation/deactivation pathway have been identified, mechanistic understanding of PDE6 regulation is limited by the lack of knowledge about the molecular organization of the PDE6 holoenzyme (αβγγ). Here, we characterize the PDE6 holoenzyme by integrative structural determination of the PDE6 catalytic dimer (αβ), based primarily on chemical cross-linking and mass spectrometric analysis. Our models built from high-density cross-linking data elucidate a parallel organization of the two catalytic subunits, with juxtaposed α-helical segments within the tandem regulatory GAF domains to provide multiple sites for dimerization. The two catalytic domains exist in an open configuration when compared to the structure of PDE2 in the apo state. Detailed structural elements for differential binding of the γ-subunit to the GAFa domains of the α- and β-subunits are revealed, providing insight into the regulation of the PDE6 activation/deactivation cycle.

Original languageAmerican English
Pages (from-to)3713-3728
Number of pages16
JournalJournal of Molecular Biology
Volume426
Issue number22
DOIs
StatePublished - 11 Nov 2014
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2014 Elsevier Ltd. All rights reserved.

Keywords

  • chemical cross-linking
  • integrative modeling
  • mass spectrometry
  • phosphodiesterase 6 (PDE6)
  • visual transduction

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