Structural Analysis of a Metamorphic Protein using AlphaFold2
Tyree, S.; Kim, Y.
Show abstract
Metamorphic proteins, which can adopt multiple stable conformations, challenge the traditional understanding of protein structure and function. KaiB is a metamorphic protein that regulates the circadian clock, a central regulator governing gene expression in most light-perceiving organisms on Earth. An interesting aspect is that the circadian clock can be reconstituted in vitro by mixing Kai proteins (KaiA, KaiB, and KaiC) with ATP and Mg2+. The phosphorylation state of KaiC oscillates with a 24-hour period. The fold-switched form of KaiB binds to KaiC to activate the dephosphorylation of KaiC, while the other fold of KaiB dissociates from KaiC, allowing phosphorylation to be activated by the binding of KaiA to KaiC. To understand the metamorphic process of KaiB, we utilized AlphaFold2, a protein structure prediction program, and sequence alignments. We found that a proline residue determines the fold of KaiB. We also confirmed that mutating this proline to lysine changes KaiB to a fold-switched conformation. This validates that AlphaFold2 can be used for the study of metamorphic proteins.
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