The mechanism by which a propeptide-encoded pH sensor regulates spatiotemporal activation of furin.

ABSTRACT: The proprotein convertase furin requires the pH gradient of the secretory pathway to regulate its multistep, compartment-specific autocatalytic activation. Although His-69 within the furin prodomain serves as the pH sensor that detects transport of the propeptide-enzyme complex to the trans-Golgi network, where it promotes cleavage and release of the inhibitory propeptide, a mechanistic understanding of how His-69 protonation mediates furin activation remains unclear. Here we employ biophysical, biochemical, and computational approaches to elucidate the mechanism underlying the pH-dependent activation of furin. Structural analyses and binding experiments comparing the wild-type furin propeptide with a nonprotonatable His-69 → Leu mutant that blocks furin activation in vivo revealed protona

SUBMITTER: Williamson DM 

PROVIDER: S-EPMC3696687 | biostudies-literature | 2013 Jun

REPOSITORIES: biostudies-literature