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Article

Members of the GADD45 Protein Family Show Distinct Propensities to form Toxic Amyloid-Like Aggregates in Physiological Conditions

1
IRCCS SDN, Napoli, Via E. Gianturco 113, 80143 Napoli, Italy
2
Institute of Biostructures and Bioimaging, C.N.R., Via Mezzocannone 16, 80134 Napoli, Italy
*
Authors to whom correspondence should be addressed.
Equally contributed.
Academic Editor: Vladimir N. Uversky
Int. J. Mol. Sci. 2021, 22(19), 10700; https://doi.org/10.3390/ijms221910700
Received: 31 August 2021 / Revised: 28 September 2021 / Accepted: 30 September 2021 / Published: 2 October 2021
(This article belongs to the Section Macromolecules)
The three members (GADD45α, GADD45β, and GADD45γ) of the growth arrest and DNA damage-inducible 45 (GADD45) protein family are involved in a myriad of diversified cellular functions. With the aim of unravelling analogies and differences, we performed comparative biochemical and biophysical analyses on the three proteins. The characterization and quantification of their binding to the MKK7 kinase, a validated functional partner of GADD45β, indicate that GADD45α and GADD45γ are strong interactors of the kinase. Despite their remarkable sequence similarity, the three proteins present rather distinct biophysical properties. Indeed, while GADD45β and GADD45γ are marginally stable at physiological temperatures, GADD45α presents the Tm value expected for a protein isolated from a mesophilic organism. Surprisingly, GADD45α and GADD45β, when heated, form high-molecular weight species that exhibit features (ThT binding and intrinsic label-free UV/visible fluorescence) proper of amyloid-like aggregates. Cell viability studies demonstrate that they are endowed with a remarkable toxicity against SHSY-5Y and HepG2 cells. The very uncommon property of GADD45β to form cytotoxic species in near-physiological conditions represents a puzzling finding with potential functional implications. Finally, the low stability and/or the propensity to form toxic species of GADD45 proteins constitute important features that should be considered in interpreting their many functions. View Full-Text
Keywords: protein aggregation; amyloid-like toxicity; structure-stability relationships protein aggregation; amyloid-like toxicity; structure-stability relationships
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MDPI and ACS Style

Smaldone, G.; Caruso, D.; Sandomenico, A.; Iaccarino, E.; Focà, A.; Ruggiero, A.; Ruvo, M.; Vitagliano, L. Members of the GADD45 Protein Family Show Distinct Propensities to form Toxic Amyloid-Like Aggregates in Physiological Conditions. Int. J. Mol. Sci. 2021, 22, 10700. https://doi.org/10.3390/ijms221910700

AMA Style

Smaldone G, Caruso D, Sandomenico A, Iaccarino E, Focà A, Ruggiero A, Ruvo M, Vitagliano L. Members of the GADD45 Protein Family Show Distinct Propensities to form Toxic Amyloid-Like Aggregates in Physiological Conditions. International Journal of Molecular Sciences. 2021; 22(19):10700. https://doi.org/10.3390/ijms221910700

Chicago/Turabian Style

Smaldone, Giovanni, Daniela Caruso, Annamaria Sandomenico, Emanuela Iaccarino, Annalia Focà, Alessia Ruggiero, Menotti Ruvo, and Luigi Vitagliano. 2021. "Members of the GADD45 Protein Family Show Distinct Propensities to form Toxic Amyloid-Like Aggregates in Physiological Conditions" International Journal of Molecular Sciences 22, no. 19: 10700. https://doi.org/10.3390/ijms221910700

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