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Article

Cu(II) Binding Increases the Soluble Toxicity of Amyloidogenic Light Chains

by
Rosaria Russo
1,
Margherita Romeo
2,
Tim Schulte
3,
Martina Maritan
4,
Luca Oberti
4,
Maria Monica Barzago
2,
Alberto Barbiroli
5,
Carlo Pappone
3,6,7,
Luigi Anastasia
3,7,
Giovanni Palladini
8,
Luisa Diomede
2,* and
Stefano Ricagno
3,4,*
1
Dipartimento di Fisiopatologia Medico-Chirurgica e Dei Trapianti, Università Degli Studi di Milano, 20090 Segrate, Italy
2
Dipartimento di Biochimica e Farmacologia Molecolare, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, 20156 Milan, Italy
3
Institute of Molecular and Translational Cardiology, IRCCS Policlinico San Donato, 20097 Milan, Italy
4
Dipartimento di Bioscienze, Università Degli Studi di Milano, 20133 Milano, Italy
5
Dipartimento di Scienze per gli Alimenti, La Nutrizione e L’Ambiente, Università Degli Studi di Milano, 20133 Milan, Italy
6
Arrhythmia and Electrophysiology Department, IRCCS Policlinico San Donato, San Donato, 20097 Milan, Italy
7
Faculty of Medicine and Surgery, Vita-Salute San Raffaele University, 20132 Milan, Italy
8
Amyloidosis Treatment and Research Center, Fondazione IRCCS Policlinico San Matteo, Università Degli Studi di Pavia, 27100 Pavia, Italy
*
Authors to whom correspondence should be addressed.
Int. J. Mol. Sci. 2022, 23(2), 950; https://doi.org/10.3390/ijms23020950
Submission received: 13 December 2021 / Revised: 10 January 2022 / Accepted: 12 January 2022 / Published: 16 January 2022
(This article belongs to the Special Issue Protein Folding Diseases—Molecular Mechanisms and Therapeutic Approaches)
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Abstract

Light chain amyloidosis (AL) is caused by the aberrant overproduction of immunoglobulin light chains (LCs). The resulting abnormally high LC concentrations in blood lead to deposit formation in the heart and other target organs. Organ damage is caused not only by the accumulation of bulky amyloid deposits, but extensive clinical data indicate that circulating soluble LCs also exert cardiotoxic effects. The nematode C. elegans has been validated to recapitulate LC soluble toxicity in vivo, and in such a model a role for copper ions in increasing LC soluble toxicity has been reported. Here, we applied microscale thermophoresis, isothermal calorimetry and thermal melting to demonstrate the specific binding of Cu2+ to the variable domain of amyloidogenic H7 with a sub-micromolar affinity. Histidine residues present in the LC sequence are not involved in the binding, and yet their mutation to Ala reduces the soluble toxicity of H7. Copper ions bind to and destabilize the variable domains and induce a limited stabilization in this domain. In summary, the data reported here, elucidate the biochemical bases of the Cu2+-induced toxicity; moreover, they also show that copper binding is just one of the several biochemical traits contributing to LC soluble in vivo toxicity.
Keywords: light chain amyloidosis; soluble toxicity; protein aggregation; copper ions; copper binding light chain amyloidosis; soluble toxicity; protein aggregation; copper ions; copper binding

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MDPI and ACS Style

Russo, R.; Romeo, M.; Schulte, T.; Maritan, M.; Oberti, L.; Barzago, M.M.; Barbiroli, A.; Pappone, C.; Anastasia, L.; Palladini, G.; et al. Cu(II) Binding Increases the Soluble Toxicity of Amyloidogenic Light Chains. Int. J. Mol. Sci. 2022, 23, 950. https://doi.org/10.3390/ijms23020950

AMA Style

Russo R, Romeo M, Schulte T, Maritan M, Oberti L, Barzago MM, Barbiroli A, Pappone C, Anastasia L, Palladini G, et al. Cu(II) Binding Increases the Soluble Toxicity of Amyloidogenic Light Chains. International Journal of Molecular Sciences. 2022; 23(2):950. https://doi.org/10.3390/ijms23020950

Chicago/Turabian Style

Russo, Rosaria, Margherita Romeo, Tim Schulte, Martina Maritan, Luca Oberti, Maria Monica Barzago, Alberto Barbiroli, Carlo Pappone, Luigi Anastasia, Giovanni Palladini, and et al. 2022. "Cu(II) Binding Increases the Soluble Toxicity of Amyloidogenic Light Chains" International Journal of Molecular Sciences 23, no. 2: 950. https://doi.org/10.3390/ijms23020950

APA Style

Russo, R., Romeo, M., Schulte, T., Maritan, M., Oberti, L., Barzago, M. M., Barbiroli, A., Pappone, C., Anastasia, L., Palladini, G., Diomede, L., & Ricagno, S. (2022). Cu(II) Binding Increases the Soluble Toxicity of Amyloidogenic Light Chains. International Journal of Molecular Sciences, 23(2), 950. https://doi.org/10.3390/ijms23020950

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