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Structural Characterization of Whirlin Reveals an Unexpected and Dynamic Supramodule Conformation of Its PDZ Tandem.

Authors
  • Delhommel, Florent1
  • Cordier, Florence2
  • Bardiaux, Benjamin3
  • Bouvier, Guillaume3
  • Colcombet-Cazenave, Baptiste2
  • Brier, Sébastien4
  • Raynal, Bertrand5
  • Nouaille, Sylvie6
  • Bahloul, Amel6
  • Chamot-Rooke, Julia4
  • Nilges, Michael3
  • Petit, Christine7
  • Wolff, Nicolas8
  • 1 Sorbonne Universités, UPMC Université Paris 06, Complexité du Vivant, 75005 Paris, France; CNRS, UMR 3528, 75015 Paris, France; Unité de Résonance Magnétique Nucléaire des Biomolécules, Institut Pasteur, 75015 Paris, France. , (France)
  • 2 CNRS, UMR 3528, 75015 Paris, France; Unité de Résonance Magnétique Nucléaire des Biomolécules, Institut Pasteur, 75015 Paris, France. , (France)
  • 3 CNRS, UMR 3528, 75015 Paris, France; Unité de Bio-Informatique Structurale, Institut Pasteur, 75015 Paris, France. , (France)
  • 4 CNRS, UMR 3528, 75015 Paris, France; Unité de Spectrométrie de Masse Structurale et Protéomique, Institut Pasteur, 75015 Paris, France. , (France)
  • 5 CNRS, UMR 3528, 75015 Paris, France; Plateforme de Biophysique Moléculaire, Institut Pasteur, 75015 Paris, France. , (France)
  • 6 Sorbonne Universités, UPMC Université Paris 06, Complexité du Vivant, 75005 Paris, France; Unité de Génétique et physiologie de l'audition, Institut Pasteur, 75015 Paris, France; Unité Mixte de Recherche, UMRS 1120, Institut National de la Santé et de la Recherche Médicale (INSERM), 75015 Paris, France. , (France)
  • 7 Sorbonne Universités, UPMC Université Paris 06, Complexité du Vivant, 75005 Paris, France; Unité de Génétique et physiologie de l'audition, Institut Pasteur, 75015 Paris, France; Unité Mixte de Recherche, UMRS 1120, Institut National de la Santé et de la Recherche Médicale (INSERM), 75015 Paris, France; Collège de France, 75005 Paris, France. , (France)
  • 8 CNRS, UMR 3528, 75015 Paris, France; Unité de Résonance Magnétique Nucléaire des Biomolécules, Institut Pasteur, 75015 Paris, France. Electronic address: [email protected] , (France)
Type
Published Article
Journal
Structure
Publisher
Elsevier
Publication Date
Nov 07, 2017
Volume
25
Issue
11
Identifiers
DOI: 10.1016/j.str.2017.08.013
PMID: 28966015
Source
Medline
Keywords
License
Unknown

Abstract

Hearing relies on the transduction of sound-evoked vibrations into electric signals, occurring in the stereocilia bundle of hair cells. The bundle is organized in a staircase pattern formed by rows of packed stereocilia. This architecture is pivotal to transduction and involves a network of scaffolding proteins with hitherto uncharacterized features. Key interactions in this network are mediated by PDZ domains. Here, we describe the architecture of the first two PDZ domains of whirlin, a protein involved in these assemblies and associated with congenital deaf-blindness. C-terminal hairpin extensions of the PDZ domains mediate the transient supramodular assembly, which improves the binding capacity of the first domain. We determined a detailed structural model of the closed conformation of the PDZ tandem and characterized its equilibrium with an ensemble of open conformations. The structural and dynamic behavior of this PDZ tandem provides key insights into the regulatory mechanisms involved in the hearing machinery.

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