Structural Basis for the Acceleration of Procollagen Processing by Procollagen C-Proteinase Enhancer-1

Procollagen C-proteinase enhancer-1 (PCPE-1) is a secreted protein that specifically accelerates proteolytic release of the C-propeptides from fibrillar procollagens, a crucial step in fibril assembly. As such, it is a potential therapeutic target to improve tissue repair and prevent fibrosis, a major cause of mortality worldwide. Here we present the crystal structure of the active CUB1CUB2 fragment of PCPE-1 bound to the C-propeptide trimer of procollagen III (CPIII). This shows that the two CUB domains bind to two different chains of CPIII and that the N-terminal region of one CPIII chain, close to the proteolytic cleavage site, lies in the cleft between CUB1 and CUB2. This suggests that enhancing activity involves unraveling of this chain from the rest of the trimer, thus facilitating the action of the proteinase involved. Support for this hypothesis comes from site-directed mutagenesis, enzyme assays, binding studies, and molecular modeling. [Display omitted] •The crystal structure of PCPE-1 bound to the C-propeptides has been determined•The N terminus of one propeptide chain binds to the CUB1CUB2 fragment of PCPE-1•PCPE-1 seems to unravel the propeptide trimer to enable proteolytic release•Molecular modeling with the proteinase and its substrate supports this hypothesis Collagens are the most abundant proteins in mammals. Fiber-forming collagens are synthesized as procollagens, where the C-propeptides are released by specific proteinases (BMP-1). C-propeptide release is accelerated by another extracellular matrix protein called PCPE-1. Here, based on structural data, the authors present a mechanism for the acceleration of C-propeptide release.