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.
Original language | American English |
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Pages (from-to) | 10648-10656 |
Number of pages | 9 |
Journal | Journal of Physical Chemistry B |
Volume | 121 |
Issue number | 47 |
DOIs | |
State | Published - 30 Nov 2017 |
Bibliographical note
Funding Information:R.N., R.M., and P.A.J. acknowledge the support of NSF-MCB-1613462 (R.M.), BSF Grant 2015831 (R.N.), and NIH Grant GM101467 (P.A.J.). We acknowledge the computing time granted by JARA-HPC and very fruitful discussions with Prof. Maria Ramos.
Publisher Copyright:
© 2017 American Chemical Society.