Structural and dynamic characterization of the C-terminal tail of ErbB2: disordered but not random
Résumé
ErbB2 (or HER2) is a receptor tyrosine kinase overexpressed in some breast cancers, associated with poor
prognosis. Treatments targeting the receptor extracellular and kinase domains have greatly improved disease outcome in the
last twenty years. In parallel, the structures of these domains have been described, enabling better mechanistic understanding of
the receptor function and targeted inhibition. However, ErbB2 disordered C-terminal cytoplasmic tail (CtErbB2) remains very
poorly characterized in terms of structure, dynamics and detailed functional mechanism. Yet, it is where signal transduction is
triggered, via phosphorylation of tyrosine residues, and carried out, via interaction with adaptor proteins. Here we report the first
description of ErbB2 disordered tail at atomic resolution using NMR, complemented by SAXS. We show that although no part of
CtErbB2 has any fully populated secondary or tertiary structure, it contains several transient helices and numerous transient
PPII helices, populated up to 20 and 40% respectively, and low but significant compaction. The presence of some structural
elements suggests, along the lines of the results obtained for EGFR (ErbB1), that they may have a functional role in ErbB2’s
auto-regulation processes. In addition, the transient formation of PPII helices is compliant with previously suggested interactions
with SH3 domains. All in all, our in-depth structural study opens new perspectives in the mechanistic understanding of ErbB2.
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