forkheadassociated

Forkhead-associated (FHA) domain is a protein domain of about 90-100 amino acids found in a variety of eukaryotic signaling and DNA damage response proteins. It functions as a phosphothreonine-binding module, recognizing phosphorylated threonine residues within specific sequence contexts and enabling regulated protein-protein interactions during checkpoint signaling.

Structure and binding: The FHA domain adopts a beta-sandwich fold. A conserved basic pocket coordinates the phosphate group of a phosphothreonine, and contacts with surrounding residues determine specificity for particular motifs. Phosphorylation state of the target is essential for binding, and some FHA domains have preferences for residues adjacent to the phosphothreonine.

Distribution and function: FHA domains are widespread in proteins involved in cell cycle control, DNA damage response, and maintenance of genome stability. They commonly occur in kinases, adaptor proteins, and scaffold proteins, sometimes in tandem repeats, and are often positioned to recruit downstream effectors to sites of DNA damage or replication stress. In many signaling pathways, FHA-mediated interactions help propagate checkpoints and coordinate repair with cell cycle progression.

Examples and significance: In humans, CHK2 (checkpoint kinase 2) contains an FHA domain; in the yeast Saccharomyces cerevisiae, Rad53 carries two FHA domains; the human NBN (nibrin) protein also contains an FHA domain. Mutations that disrupt FHA function can impair checkpoint signaling and contribute to genome instability and cancer susceptibility.

See also: protein domains, phosphothreonine recognition.