Intrinsically disordered N-terminal regions suppress cotranslational protein degradation

Intrinsically disordered regions (IDRs) of proteins are thought to be inherently sensitive to proteolysis and considered one of the key components constituting an efficient degron. Here we report that IDRs can also suppress protein degradation. Our recent study showed that yeast ribosomal proteins, while posttranslationally stable, are subject to cotranslational protein degradation (CTPD). In mapping the degron responsible for CTPD of ribosomal protein Rpl8A, we found that its N-terminal IDR suppresses CTPD, whereas the adjacent structured domain acts as a degron. We further assessed the N-terminal IDRs of 9 other yeast proteins and found that they all inhibit CTPD. These results suggest that suppression of CTPD is likely a generic function of N-terminal IDRs. Moreover, we showed that the N-terminal IDR of human ribosomal protein hRpl7A also functions as a stabilizer against CTPD in human cells. When transplanted to the N-terminus of cystic fibrosis transmembrane conductance regulator (CFTR), the N-terminal IDR of hRpl7A reduces CTPD of CFTR by more than 80%. Thus, the stabilizer function of N-terminal IDRs is conserved from yeast to human. Using mass spectrometry, we demonstrated that HSP70 chaperone proteins Ssa and Ssb bind to the N-terminal IDR of Rpl8A. These data suggest that N-terminal IDRs may inhibit CTPD through recruiting HSP70 chaperone proteins to nascent chains, thereby facilitating cotranslational folding. Our study unveils a new role for IDRs in suppressing CTPD.