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Molecular Dynamics Simulations of the [2Fe-2S] Cluster-Binding Domain of NEET Proteins Reveal Key Molecular Determinants That Induce Their Cluster Transfer/Release.


ABSTRACT: The NEET proteins are a novel family of iron-sulfur proteins characterized by an unusual three cysteine and one histidine coordinated [2Fe-2S] cluster. Aberrant cluster release, facilitated by the breakage of the Fe-N bond, is implicated in a variety of human diseases, including cancer. Here, the molecular dynamics in the multi-microsecond timescale, along with quantum chemical calculations, on two representative members of the family (the human NAF-1 and mitoNEET proteins), show that the loss of the cluster is associated with a dramatic decrease in secondary and tertiary structure. In addition, the calculations provide a mechanism for cluster release and clarify, for the first time, crucial differences existing between the two proteins, which are reflected in the experimentally observed difference in the pH-dependent cluster reactivity. The reliability of our conclusions is established by an extensive comparison with the NMR data of the solution proteins, in part measured in this work.

SUBMITTER: Pesce L 

PROVIDER: S-EPMC5713697 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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Molecular Dynamics Simulations of the [2Fe-2S] Cluster-Binding Domain of NEET Proteins Reveal Key Molecular Determinants That Induce Their Cluster Transfer/Release.

Pesce Luca L   Calandrini Vania V   Marjault Henri-Baptiste HB   Lipper Colin H CH   Rossetti Gulia G   Mittler Ron R   Jennings Patricia A PA   Bauer Andreas A   Nechushtai Rachel R   Carloni Paolo P  

The journal of physical chemistry. B 20171116 47


The NEET proteins are a novel family of iron-sulfur proteins characterized by an unusual three cysteine and one histidine coordinated [2Fe-2S] cluster. Aberrant cluster release, facilitated by the breakage of the Fe-N bond, is implicated in a variety of human diseases, including cancer. Here, the molecular dynamics in the multi-microsecond timescale, along with quantum chemical calculations, on two representative members of the family (the human NAF-1 and mitoNEET proteins), show that the loss o  ...[more]

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