ABSTRACT
Forkhead-associated (FHA) domains are small phosphopeptide recognition modules found in eubacterial and eukaryotic, but not archeal, genomes. Although they were originally found in forkhead-type transcription factors, they have now been identified in many other signaling proteins. FHA domains share a remarkably conserved fold despite very low sequence conservation. They only have five conserved amino acids that are important for binding to phosphorylated epitopes. Recent work from several laboratories has demonstrated that FHA domains can mediate many interactions that do not depend on their ability to recognize a phosphorylated threonine. In this review, we present structural and biochemical work that has unveiled novel interaction interfaces on FHA domains. We discuss how these non-canonical interactions modulate the recognition of phosphorylated and non-phosphorylated substrates, as well as protein oligomerization - events that collectively determine FHA function.