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Common features in the unfolding and misfolding of PDZ domains and beyond: the modulatory effect of domain swapping and extra-elements

Murciano-Calles, Javier and Güell-Bosch, Jofre and Villegas, Sandra and Martinez, Jose C. (2016) Common features in the unfolding and misfolding of PDZ domains and beyond: the modulatory effect of domain swapping and extra-elements. Scientific Reports, 6 . Art. No. 19242. ISSN 2045-2322. PMCID PMC4709687. doi:10.1038/srep19242.

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PDZ domains are protein-protein interaction modules sharing the same structural arrangement. To discern whether they display common features in their unfolding/misfolding behaviour we have analyzed in this work the unfolding thermodynamics, together with the misfolding kinetics, of the PDZ fold using three archetypical examples: the second and third PDZ domains of the PSD95 protein and the Erbin PDZ domain. Results showed that all domains passed through a common intermediate, which populated upon unfolding, and that this in turn drove the misfolding towards worm-like fibrillar structures. Thus, the unfolding/misfolding behaviour appears to be shared within these domains. We have also analyzed how this landscape can be modified upon the inclusion of extra-elements, as it is in the nNOS PDZ domain, or the organization of swapped species, as happens in the second PDZ domain of the ZO2 protein. Although the intermediates still formed upon thermal unfolding, the misfolding was prevented to varying degrees.

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Additional Information:This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit Received: 08 October 2015. Accepted: 08 December 2015. Published online: 12 January 2016. This research was supported by grants CVI-5915 from the Junta de Andalucía, BIO2012-39922-C02 from the Ministerio de Economia y Competitividad and FEDER, PI13-01330 from Instituto de Salud Carlos III and SGR09-0761 from the Generalitat de Catalunya. J M-C. received a postdoctoral contract from the Ministerio de Economia y Competitividad and presently acknowledges financial support from the Alfonso Martín Escudero Foundation. We specially acknowledge Dr. David K. Romney for revising and correcting our English text. We are also grateful to Dr. Javier Ruiz-Sanz for its criticisms and technical help. Contributions: J.C.M. planned the research project; J.M.-C. and J.G.-B. performed research experiments; J.M.-C. and J.C.M. wrote the manuscript; all authors analyzed data, prepared figures and Supplementary Information, and revised the manuscript. The authors declare no competing financial interests.
Funding AgencyGrant Number
Junta de AndalucíaCVI-5915
Ministerio de Economía y Competitividad (MINECO)BIO2012-39922-C02
Federación Española de Enfermedades Raras (FEDER)UNSPECIFIED
Instituto de Salud Carlos IIIPI13-01330
Generalitat de CatalunyaSGR09-0761
Alfonso Martín Escudero FoundationUNSPECIFIED
PubMed Central ID:PMC4709687
Record Number:CaltechAUTHORS:20160204-142513864
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Official Citation:Murciano-Calles, J. et al. Common features in the unfolding and misfolding of PDZ domains and beyond: the modulatory effect of domain swapping and extra-elements. Sci. Rep. 6, 19242; doi: 10.1038/srep19242 (2016).
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:64237
Deposited By: George Porter
Deposited On:04 Feb 2016 22:45
Last Modified:10 Nov 2021 23:27

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