FoxP3 can fold into two distinct dimerization states with divergent functional implications for T cell homeostasis

Abstract

AbstractFoxP3 is an essential transcription factor (TF) for immunologic homeostasis, but how it utilizes the common forkhead DNA-binding domain (DBD) to perform its unique function remains poorly understood. We here demonstrate that, unlike other known forkhead TFs, FoxP3 forms a head-to-head dimer using a unique linker (Runx1-binding region, RBR) preceding the forkhead domain. Head-to-head dimerization confers distinct DNA-binding specificity and creates a docking site for the cofactor Runx1. RBR is also important for proper folding of the forkhead domain, as truncation of RBR induces domain-swap dimerization of forkhead, which was previously considered the physiological form of FoxP3. Rather, swap-dimerization impairs FoxP3 function, as demonstrated with the disease-causing mutation R337Q, while a swap-suppressive mutation largely rescues R337Q-mediated functional impairment. Altogether, our findings suggest that FoxP3 can fold into two distinct dimerization states: head-to-head dimerization representing functional specialization of an ancient DBD and swap-dimerization with impaired functions.