Charged residues distribution modulates selectivity of the open state of human isoforms of the voltage dependent anion-selective channel.

Voltage Dependent Anion-selective Channels (VDACs) are pore-forming proteins located in the outer mitochondrial membrane. They are responsible for the access of ions and energetic metabolites into the inner membrane transport systems. Three VDAC isoforms exist in mammalian, but their specific role i...

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Autores principales:	Giuseppe Federico Amodeo, Mariano Andrea Scorciapino, Angela Messina, Vito De Pinto, Matteo Ceccarelli
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2014
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/aaad390f03454faf80df6ff946c64f56
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spelling	oai:doaj.org-article:aaad390f03454faf80df6ff946c64f562021-11-25T06:06:17ZCharged residues distribution modulates selectivity of the open state of human isoforms of the voltage dependent anion-selective channel.1932-620310.1371/journal.pone.0103879https://doaj.org/article/aaad390f03454faf80df6ff946c64f562014-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/25084457/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203Voltage Dependent Anion-selective Channels (VDACs) are pore-forming proteins located in the outer mitochondrial membrane. They are responsible for the access of ions and energetic metabolites into the inner membrane transport systems. Three VDAC isoforms exist in mammalian, but their specific role is unknown. In this work we have performed extensive (overall ∼5 µs) Molecular Dynamics (MD) simulations of the human VDAC isoforms to detect structural and conformational variations among them, possibly related to specific functional roles of these proteins. Secondary structure analysis of the N-terminal domain shows a high similarity among the three human isoforms of VDAC but with a different plasticity. In particular, the N-terminal domain of the hVDAC1 is characterized by a higher plasticity, with a ∼20% occurrence for the 'unstructured' conformation throughout the folded segment, while hVDAC2, containing a peculiar extension of 11 amino acids at the N-terminal end, presents an additional 310-helical folded portion comprising residues 10' to 3, adhering to the barrel wall. The N-terminal sequences of hVDAC isoforms are predicted to have a low flexibility, with possible consequences in the dynamics of the human VDACs. Clear differences were found between hVDAC1 and hVDAC3 against hVDAC2: a significantly modified dynamics with possible important consequence on the voltage-gating mechanism. Charge distribution inside and at the mouth of the pore is responsible for a different preferential localization of ions with opposite charge and provide a valuable rationale for hVDAC1 and hVDAC3 having a Cl-/K+ selectivity ratio of 1.8, whereas hVDAC2 of 1.4. Our conclusion is that hVDAC isoforms, despite sharing a similar scaffold, have modified working features and a biological work is now requested to give evidence to the described dissimilarities.Giuseppe Federico AmodeoMariano Andrea ScorciapinoAngela MessinaVito De PintoMatteo CeccarelliPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 9, Iss 8, p e103879 (2014)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Giuseppe Federico Amodeo Mariano Andrea Scorciapino Angela Messina Vito De Pinto Matteo Ceccarelli Charged residues distribution modulates selectivity of the open state of human isoforms of the voltage dependent anion-selective channel.
description	Voltage Dependent Anion-selective Channels (VDACs) are pore-forming proteins located in the outer mitochondrial membrane. They are responsible for the access of ions and energetic metabolites into the inner membrane transport systems. Three VDAC isoforms exist in mammalian, but their specific role is unknown. In this work we have performed extensive (overall ∼5 µs) Molecular Dynamics (MD) simulations of the human VDAC isoforms to detect structural and conformational variations among them, possibly related to specific functional roles of these proteins. Secondary structure analysis of the N-terminal domain shows a high similarity among the three human isoforms of VDAC but with a different plasticity. In particular, the N-terminal domain of the hVDAC1 is characterized by a higher plasticity, with a ∼20% occurrence for the 'unstructured' conformation throughout the folded segment, while hVDAC2, containing a peculiar extension of 11 amino acids at the N-terminal end, presents an additional 310-helical folded portion comprising residues 10' to 3, adhering to the barrel wall. The N-terminal sequences of hVDAC isoforms are predicted to have a low flexibility, with possible consequences in the dynamics of the human VDACs. Clear differences were found between hVDAC1 and hVDAC3 against hVDAC2: a significantly modified dynamics with possible important consequence on the voltage-gating mechanism. Charge distribution inside and at the mouth of the pore is responsible for a different preferential localization of ions with opposite charge and provide a valuable rationale for hVDAC1 and hVDAC3 having a Cl-/K+ selectivity ratio of 1.8, whereas hVDAC2 of 1.4. Our conclusion is that hVDAC isoforms, despite sharing a similar scaffold, have modified working features and a biological work is now requested to give evidence to the described dissimilarities.
format	article
author	Giuseppe Federico Amodeo Mariano Andrea Scorciapino Angela Messina Vito De Pinto Matteo Ceccarelli
author_facet	Giuseppe Federico Amodeo Mariano Andrea Scorciapino Angela Messina Vito De Pinto Matteo Ceccarelli
author_sort	Giuseppe Federico Amodeo
title	Charged residues distribution modulates selectivity of the open state of human isoforms of the voltage dependent anion-selective channel.
title_short	Charged residues distribution modulates selectivity of the open state of human isoforms of the voltage dependent anion-selective channel.
title_full	Charged residues distribution modulates selectivity of the open state of human isoforms of the voltage dependent anion-selective channel.
title_fullStr	Charged residues distribution modulates selectivity of the open state of human isoforms of the voltage dependent anion-selective channel.
title_full_unstemmed	Charged residues distribution modulates selectivity of the open state of human isoforms of the voltage dependent anion-selective channel.
title_sort	charged residues distribution modulates selectivity of the open state of human isoforms of the voltage dependent anion-selective channel.
publisher	Public Library of Science (PLoS)
publishDate	2014
url	https://doaj.org/article/aaad390f03454faf80df6ff946c64f56
work_keys_str_mv	AT giuseppefedericoamodeo chargedresiduesdistributionmodulatesselectivityoftheopenstateofhumanisoformsofthevoltagedependentanionselectivechannel AT marianoandreascorciapino chargedresiduesdistributionmodulatesselectivityoftheopenstateofhumanisoformsofthevoltagedependentanionselectivechannel AT angelamessina chargedresiduesdistributionmodulatesselectivityoftheopenstateofhumanisoformsofthevoltagedependentanionselectivechannel AT vitodepinto chargedresiduesdistributionmodulatesselectivityoftheopenstateofhumanisoformsofthevoltagedependentanionselectivechannel AT matteoceccarelli chargedresiduesdistributionmodulatesselectivityoftheopenstateofhumanisoformsofthevoltagedependentanionselectivechannel
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Charged residues distribution modulates selectivity of the open state of human isoforms of the voltage dependent anion-selective channel.

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