Manipulating the Folding Landscape of a Multidomain Protein

The Journal of Physical Chemistry. B
Raisa KantaevGilad Haran

Abstract

Folding of proteins to their functional conformation is paramount to life. Though 75% of the proteome consists of multidomain proteins, our knowledge of folding has been based primarily on studies conducted on single-domain and fast-folding proteins. Nonetheless, the complexity of folding landscapes exhibited by multidomain proteins has received increased scrutiny in recent years. We study the three-domain protein adenylate kinase from E. coli (AK), which has been shown to fold through a series of pathways involving several intermediate states. We use a protein design method to manipulate the folding landscape of AK, and single-molecule FRET spectroscopy to study the effects on the folding process. Mutations introduced in the NMP binding (NMPbind) domain of the protein are found to have unexpected effects on the folding landscape. Thus, while stabilizing mutations in the core of the NMPbind domain retain the main folding pathways of wild-type AK, a destabilizing mutation at the interface between the NMPbind and the CORE domains causes a significant repartition of the flux between the folding pathways. Our results demonstrate the outstanding plasticity of the folding landscape of AK and reveal how specific mutations in the prima...Continue Reading

Citations

Nov 13, 2019·The Journal of Biological Chemistry·Anne GershensonPatrick L Wintrode
Aug 5, 2020·Proceedings of the National Academy of Sciences of the United States of America·Candice GautierStefano Gianni
Feb 2, 2021·The Journal of Biological Chemistry·Anne GershensonPatrick L Wintrode
Nov 22, 2020·Current Opinion in Structural Biology·Lisa J Lapidus
May 5, 2021·Chembiochem : a European Journal of Chemical Biology·Kim BartelsChristian Löw
Jun 6, 2021·Journal of Molecular Biology·Livia PaganoStefano Gianni

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