Research ArticleStructural Biology

Structural insights into the functional versatility of an FHA domain protein in mycobacterial signaling

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Science Signaling  07 May 2019:
Vol. 12, Issue 580, eaav9504
DOI: 10.1126/scisignal.aav9504

An FHA domain with dual specificity

Forkhead-associated (FHA) domains participate in phosphorylation-dependent signaling pathways by binding to phosphothreonine. As part of a signaling pathway that controls glutamate metabolism, the mycobacterial FHA domain–containing protein GarA binds to both phosphorylated upstream partners, such as the kinases PknB and PknG, and nonphosphorylated downstream partners, such as the 2-oxoglutarate decarboxylase KGD. Through biochemical and structural studies, Wagner et al. found that the interactions of GarA with both phosphorylated PknB and nonphosphorylated KGD were mediated by the phosphate-binding pocket of the FHA domain, which bound to a phosphothreonine in the activation loop of PknB and to a phosphomimetic aspartate residue in KGD. In addition to illustrating the dual binding specificity of GarA, these findings demonstrate a physiological role for aspartate as a phosphomimetic.

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