Hidden α-helical propensity segments within disordered regions of the transcriptional activator CHOP.

C/EBP-homologous protein (CHOP) is a key determinant of the apoptotic response to endoplasmic reticulum stress or DNA damage. As a member of the C/EBP family, CHOP contains a low complexity N-terminal region involved in transcriptional activation, followed by a bZIP that binds DNA after dimerization. However, in contrast to other C/EBPs, CHOP directs binding to non-canonical C/EBP sites due to unique substitutions in its DNA-binding domain. Herein, we show that the N-terminal region of CHOP is intrinsically unstructured but contains two segments presenting α-helical propensity. One of these segments is conserved in other C/EBPs and mediates essential roles of CHOP, including regulation through phosphorylation. The second segment is placed within a proteolytic-resistant portion of the protein and exhibits reduced flexibility. Moreover, the DNA-binding region of CHOP also contains a segment with α-helical character towards its most N-terminal part. Our results suggest that structure-prone segments scattered within disordered regions may be critical for macromolecular recognition during CHOP-mediated transcriptional activation.