1H, 13C and 15N backbone resonance assignments and dynamic properties of the PDZ tandem of Whirlin

Delhommel, Florent; Wolff, Nicolas; Cordier, Florence

doi:10.1007/s12104-016-9701-z

Cited by 6 publications

(8 citation statements)

References 17 publications

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“…The Tandem PDZ1-2 of Whirlin Forms a Supramodule We previously determined the dynamic behavior of the two N-terminal PDZ domains of whirlin by 15 N NMR relaxation measurements (Delhommel et al, 2016). The inferred correlation time of PDZ1-2 (12.6 ns) is in good agreement with the theoretical value of $11.1 ns expected for a 27 kDa globular protein and is significantly higher than the correlation time of 7.3 ns measured for the isolated domains PDZ1-Hp1 and PDZ2-Hp2 (Figures 1A and 1C).…”

Section: Resultsmentioning

confidence: 99%

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

et al. 2017

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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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Section: Resultsmentioning

confidence: 99%

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

et al. 2017

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“…In the case of Whirlin, the anchoring to Usher protein via its PDZ1 domain guarantees mechanical communication from the surface of the stereocilia to the actin filaments, ensuring the hearing of sound waves. It is intriguing that the presence of two PDZ domains is almost universally conserved in Whirlin ( 17 , 21 ), yet no physiological partners could be found for PDZ2 ( 22 , 44 ). Thus, on the basis of our findings, we speculate that the second PDZ domain, enhancing the possibility of accumulating a functionally competent domain-swapped state, may represent a structural buffer to increase the repertoire of structures to conserve the anchoring to Sans, even in the presence of mechanical unfolding.…”

Section: Discussionmentioning

confidence: 99%

Hidden kinetic traps in multidomain folding highlight the presence of a misfolded but functionally competent intermediate

Gautier

Troilo

Cordier

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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Although more than 75% of the proteome is composed of multidomain proteins, current knowledge of protein folding is based primarily on studies of isolated domains. In this work, we describe the folding mechanism of a multidomain tandem construct comprising two distinct covalently bound PDZ domains belonging to a protein called Whirlin, a scaffolding protein of the hearing apparatus. In particular, via a synergy between NMR and kinetic experiments, we demonstrate the presence of a misfolded intermediate that competes with productive folding. In agreement with the view that tandem domain swapping is a potential source of transient misfolding, we demonstrate that such a kinetic trap retains native-like functional activity, as shown by the preserved ability to bind its physiological ligand. Thus, despite the general knowledge that protein misfolding is intimately associated with dysfunction and diseases, we provide a direct example of a functionally competent misfolded state. Remarkably, a bioinformatics analysis of the amino acidic sequence of Whirlin from different species suggests that the tendency to perform tandem domain swapping between PDZ1 and PDZ2 is highly conserved, as demonstrated by their unexpectedly high sequence identity. On the basis of these observations, we discuss on a possible physiological role of such misfolded intermediate.

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“…Stereocilia, the actin‐based protrusions on auditory and vestibular sensory cells, are required for hearing and balance (Ciuman, ; Goutman et al, ; Pan and Holt, ; Lim and Brichta, ). They convert physical force from sound, head movement, or gravity into an electrical signal, a process that is called mechano‐electrical transduction (MET) (Horwitz et al, ; Delhommel et al, ; Liu et al, ; Marcotti et al, ). This function depends on the ability of sensory cells to grow stereocilia of defined lengths (Manor et al, ; Grati et al, ; Narayanan et al, ; McGrath et al, ).…”

Section: Complexity Of the Auditory Systemmentioning

confidence: 99%

“…Located at the tips of stereocilia, the MET channels are poised to detect tension induced by hair bundle deflection (Delhommel et al, ; Liu et al, ; Marcotti et al, ). In response to the mechanical stimulus of the hair bundle, the tip‐links, key components of the MET machinery, are tensioned and the MET channels open, which results in the generation of the cell receptor potential.…”

Section: Complexity Of the Auditory Systemmentioning

confidence: 99%

Signaling in the Auditory System: Implications in Hair Cell Regeneration and Hearing Function

Mittal

Debs

Nguyen

et al. 2017

Journal Cellular Physiology

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Ear is a sensitive organ involved in hearing and balance function. The complex signaling network in the auditory system plays a crucial role in maintaining normal physiological function of the ear. The inner ear comprises a variety of host signaling pathways working in synergy to deliver clear sensory messages. Any disruption, as minor as it can be, has the potential to affect this finely tuned system with temporary or permanent sequelae including vestibular deficits and hearing loss. Mutations linked to auditory symptoms, whether inherited or acquired, are being actively researched for ways to reverse, silence, or suppress them. In this article, we discuss recent advancements in understanding the pathways involved in auditory system signaling, from hair cell development through transmission to cortical centers. Our review discusses Notch and Wnt signaling, cell to cell communication through connexin and pannexin channels, and the detrimental effects of reactive oxygen species on the auditory system. There has been an increased interest in the auditory community to explore the signaling system in the ear for hair cell regeneration. Understanding signaling pathways in the auditory system will pave the way for the novel avenues to regenerate sensory hair cells and restore hearing function. J. Cell. Physiol. 232: 2710-2721, 2017. © 2016 Wiley Periodicals, Inc.

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1H, 13C and 15N backbone resonance assignments and dynamic properties of the PDZ tandem of Whirlin

Cited by 6 publications

References 17 publications

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

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

Hidden kinetic traps in multidomain folding highlight the presence of a misfolded but functionally competent intermediate

Signaling in the Auditory System: Implications in Hair Cell Regeneration and Hearing Function

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