The folding pathway of a functionally competent C-terminal domain of nucleophosmin: protein stability and denatured state residual structure.

Sara Chiarella 1 Luca Federici 2 Adele Di Matteo 1 Maurizio Brunori 1 Stefano Gianni 1
1 Department of Biochemical Sciences "Rossi Fanelli"
2 Dipartimento di Scienze Sperimentali e Cliniche
Abstract : Nucleophosmin (NPM1) is a nucleolar protein implicated in ribosome biogenesis, centrosome duplication and cell cycle control; the NPM1 gene is the most frequent target for mutations in Acute Myeloid Leukemia. Mutations map to the C-terminal domain of the protein and cause its unfolding, loss of DNA binding properties and aberrant cellular localization. Here we investigate the folding pathway and denatured state properties of a NPM1 C-terminal domain construct encompassing the last 70 residues in the reference sequence. This construct is more stable than the previously characterized domain, which consisted of the last 53 residues. Data reveal that, similarly to what was discovered for the shorter construct, also the 70-residue construct of NPM1 displays a detectable residual structure in its denatured state. The higher stability of the latter domain allows us to conclude that the denatured state is robust to changes in solvent composition and that it consists of a discrete state in equilibrium with the expanded fully unfolded conformation. This observation, which might appear as a technicality, is in fact of general importance for the understanding of the folding of proteins. The implications of our results are discussed in the context of previous works on single domain helical proteins.
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Submitted on : Wednesday, July 23, 2014 - 4:52:35 PM
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Sara Chiarella, Luca Federici, Adele Di Matteo, Maurizio Brunori, Stefano Gianni. The folding pathway of a functionally competent C-terminal domain of nucleophosmin: protein stability and denatured state residual structure.. Biochemical and Biophysical Research Communications, Elsevier, 2013, 435 (1), pp.64-8. ⟨10.1016/j.bbrc.2013.04.038⟩. ⟨pasteur-01044571⟩

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