Molecular mechanism of calcium induced trimerization of C1q-like domain of otolin-1 from human and zebrafish

Abstract The C1q superfamily includes proteins involved in innate immunity, insulin sensitivity, biomineralization and more. Among these proteins is otolin-1, which is a collagen-like protein that forms a scaffold for the biomineralization of inner ear stones in vertebrates. The globular C1q-like do...

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Autores principales:	Rafał Hołubowicz, Andrzej Ożyhar, Piotr Dobryszycki
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/2cf02340cb784622ba8f3afa3e8a2df4
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spelling	oai:doaj.org-article:2cf02340cb784622ba8f3afa3e8a2df42021-12-02T17:40:44ZMolecular mechanism of calcium induced trimerization of C1q-like domain of otolin-1 from human and zebrafish10.1038/s41598-021-92129-82045-2322https://doaj.org/article/2cf02340cb784622ba8f3afa3e8a2df42021-06-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-92129-8https://doaj.org/toc/2045-2322Abstract The C1q superfamily includes proteins involved in innate immunity, insulin sensitivity, biomineralization and more. Among these proteins is otolin-1, which is a collagen-like protein that forms a scaffold for the biomineralization of inner ear stones in vertebrates. The globular C1q-like domain (gC1q), which is the most conserved part of otolin-1, binds Ca2+ and stabilizes its collagen-like triple helix. The molecular details of the assembly of gC1q otolin-1 trimers are not known. Here, we substituted putative Ca2+-binding acidic residues of gC1q otolin-1 with alanine to analyse how alanine influences the formation of gC1q trimers. We used human and zebrafish gC1q otolin-1 to assess how evolutionary changes affected the function of the protein. Surprisingly, the mutated forms of gC1q otolin-1 trimerized even in the absence of Ca2+, although they were less stable than native proteins saturated with Ca2+. We also found that the zebrafish gC1q domain was less stable than the human homologue under all tested conditions and became stabilized at higher concentrations of Ca2+, which showed that specific interactions leading to the neutralization of the negative charge at the axis of a gC1q trimer by Ca2+ are required for the trimers to form. Moreover, human gC1q otolin-1 seems to be optimized to function at lower concentrations of Ca2+, which is consistent with reported Ca2+ concentrations in the endolymphs of fish and mammals. Our results allow us to explain the molecular mechanism of assembly of proteins from the C1q superfamily, the modulating role of Ca2+ and expand the knowledge of biomineralization of vertebrate inner ear stones: otoliths and otoconia.Rafał HołubowiczAndrzej OżyharPiotr DobryszyckiNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-17 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Rafał Hołubowicz Andrzej Ożyhar Piotr Dobryszycki Molecular mechanism of calcium induced trimerization of C1q-like domain of otolin-1 from human and zebrafish
description	Abstract The C1q superfamily includes proteins involved in innate immunity, insulin sensitivity, biomineralization and more. Among these proteins is otolin-1, which is a collagen-like protein that forms a scaffold for the biomineralization of inner ear stones in vertebrates. The globular C1q-like domain (gC1q), which is the most conserved part of otolin-1, binds Ca2+ and stabilizes its collagen-like triple helix. The molecular details of the assembly of gC1q otolin-1 trimers are not known. Here, we substituted putative Ca2+-binding acidic residues of gC1q otolin-1 with alanine to analyse how alanine influences the formation of gC1q trimers. We used human and zebrafish gC1q otolin-1 to assess how evolutionary changes affected the function of the protein. Surprisingly, the mutated forms of gC1q otolin-1 trimerized even in the absence of Ca2+, although they were less stable than native proteins saturated with Ca2+. We also found that the zebrafish gC1q domain was less stable than the human homologue under all tested conditions and became stabilized at higher concentrations of Ca2+, which showed that specific interactions leading to the neutralization of the negative charge at the axis of a gC1q trimer by Ca2+ are required for the trimers to form. Moreover, human gC1q otolin-1 seems to be optimized to function at lower concentrations of Ca2+, which is consistent with reported Ca2+ concentrations in the endolymphs of fish and mammals. Our results allow us to explain the molecular mechanism of assembly of proteins from the C1q superfamily, the modulating role of Ca2+ and expand the knowledge of biomineralization of vertebrate inner ear stones: otoliths and otoconia.
format	article
author	Rafał Hołubowicz Andrzej Ożyhar Piotr Dobryszycki
author_facet	Rafał Hołubowicz Andrzej Ożyhar Piotr Dobryszycki
author_sort	Rafał Hołubowicz
title	Molecular mechanism of calcium induced trimerization of C1q-like domain of otolin-1 from human and zebrafish
title_short	Molecular mechanism of calcium induced trimerization of C1q-like domain of otolin-1 from human and zebrafish
title_full	Molecular mechanism of calcium induced trimerization of C1q-like domain of otolin-1 from human and zebrafish
title_fullStr	Molecular mechanism of calcium induced trimerization of C1q-like domain of otolin-1 from human and zebrafish
title_full_unstemmed	Molecular mechanism of calcium induced trimerization of C1q-like domain of otolin-1 from human and zebrafish
title_sort	molecular mechanism of calcium induced trimerization of c1q-like domain of otolin-1 from human and zebrafish
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/2cf02340cb784622ba8f3afa3e8a2df4
work_keys_str_mv	AT rafałhołubowicz molecularmechanismofcalciuminducedtrimerizationofc1qlikedomainofotolin1fromhumanandzebrafish AT andrzejozyhar molecularmechanismofcalciuminducedtrimerizationofc1qlikedomainofotolin1fromhumanandzebrafish AT piotrdobryszycki molecularmechanismofcalciuminducedtrimerizationofc1qlikedomainofotolin1fromhumanandzebrafish
_version_	1718379752769716224

Molecular mechanism of calcium induced trimerization of C1q-like domain of otolin-1 from human and zebrafish

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