Structural and dynamic characterization of the C-terminal tail of ErbB2: disordered but not random

International audienceErbB2 (or HER2) is a receptor tyrosine kinase overexpressed in some breast cancers, associated with poorprognosis. Treatments targeting the receptor extracellular and kinase domains have greatly improved disease outcome in thelast twenty years. In parallel, the structures of these domains have been described, enabling better mechanistic understanding ofthe receptor function and targeted inhibition. However, ErbB2 disordered C-terminal cytoplasmic tail (CtErbB2) remains verypoorly characterized in terms of structure, dynamics and detailed functional mechanism. Yet, it is where signal transduction istriggered, via phosphorylation of tyrosine residues, and carried out, via interaction with adaptor proteins. Here we report the firstdescription of ErbB2 disordered tail at atomic resolution using NMR, complemented by SAXS. We show that although no part ofCtErbB2 has any fully populated secondary or tertiary structure, it contains several transient helices and numerous transientPPII helices, populated up to 20 and 40% respectively, and low but significant compaction. The presence of some structuralelements suggests, along the lines of the results obtained for EGFR (ErbB1), that they may have a functional role in ErbB2’sauto-regulation processes. In addition, the transient formation of PPII helices is compliant with previously suggested interactionswith SH3 domains. All in all, our in-depth structural study opens new perspectives in the mechanistic understanding of ErbB2