Section 56
Chapter 55,949

Structural basis of a rationally rewired protein-protein interface critical to bacterial signaling

Podgornaia, A.I.; Casino, P.; Marina, A.; Laub, M.T.

Structure 21(9): 1636-1647


ISSN/ISBN: 1878-4186
PMID: 23954504
DOI: 10.1016/j.str.2013.07.005
Accession: 055948975

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Two-component signal transduction systems typically involve a sensor histidine kinase that specifically phosphorylates a single, cognate response regulator. This protein-protein interaction relies on molecular recognition via a small set of residues in each protein. To better understand how these residues determine the specificity of kinase-substrate interactions, we rationally rewired the interaction interface of a Thermotoga maritima two-component system, HK853-RR468, to match that found in a different two-component system, Escherichia coli PhoR-PhoB. The rewired proteins interacted robustly with each other, but no longer interacted with the parent proteins. Analysis of the crystal structures of the wild-type and mutant protein complexes and a systematic mutagenesis study reveal how individual mutations contribute to the rewiring of interaction specificity. Our approach and conclusions have implications for studies of other protein-protein interactions and protein evolution and for the design of novel protein interfaces.

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