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Molecular mechanism and specificity of substrate binding by the E3 Ubiquitin Ligase Pellino

Upon stimulation of Toll‐like receptors or IL‐1 receptors, IL‐1 receptor associated kinases (IRAKs) are activated to initiate cascades of events that are critical in innate immune signaling pathways. The Pellino family of RING E3 ubiquitin ligases is an important regulator of IRAKs. All 3 human Pellino isoforms bind to and polyubiquitinate activated, phosphorylated IRAK1. We have determined the X‐ray crystal structure of the Pellino2 N‐terminal substrate‐binding region, which contains a previously unidentified non‐canonical example of a forkhead‐associated (FHA) domain. FHA domains are phosphoThr (pT)‐binding modules that mediate protein‐protein interactions in a variety of cell‐signaling pathways. We have shown that the canonical pT‐binding region of Pellino mediates interaction with pTs on IRAK1. We expect specificity is defined by non‐canonical features of the Pellino FHA domain and explore this with mutational analysis. We also use IRAK1 truncation variants to define a minimal region of phosphorylated IRAK1 that is sufficient for Pellino binding. This research is supported by a Career Award in the Biomedical Sciences from the Burroughs Wellcome Fund and by NIH Training Program (T32‐GM08275).