Structure of PCPE-2 in complex with the BMP-1 metalloprotease reveals the molecular basis of its mechanism of inhibition
Abstract
PCPE-2 (procollagen C-proteinase enhancer-2) is an extracellular glycoprotein playing dual functions in the regulation of BMP-1/tolloid-like proteinases. Like its homologue PCPE-1, PCPE-2 can enhance the proteolytic maturation of fibrillar procollagens, but it also acts as a potent and specific inhibitor of BMP-1 through formation of a high-affinity complex with the protease. Here, we investigated the molecular basis of this inhibitory interaction using complementary biochemical, biophysical and structural approaches. We show that the two CUB domains of PCPE-2 must be covalently linked for efficient BMP-1 binding and inhibition, consistent with cooperative engagement of the protease. Cryo-electron microscopy combined with density-guided structural modelling and hydrogen/deuterium-exchange mass spectrometry supports a bipartite interaction complex in which the CUB1 domain of PCPE-2 engages the catalytic domain of BMP-1, while the CUB2 domains of both proteins interact together. The interaction involves the calcium-binding surfaces of the PCPE-2 CUB domains that also participate in procollagen recognition, providing a structural framework for understanding the mutually exclusive interactions of PCPE-2 with BMP-1 and procollagen. Allosteric inhibition is supported by the binding of PCPE-2 CUB1 opposite to the active site cleft, leading to the shielding of the residues surrounding the S1-prime pocket, as observed by HDX-MS. Together, these findings define the architecture of the inhibitory PCPE-2/BMP-1 complex and provide the molecular basis for understanding the distinct regulatory activities of the two procollagen C-proteinase enhancers.
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BibTeX
@misc{bauer2026structure,
title = {{Structure of PCPE-2 in complex with the BMP-1 metalloprotease reveals the molecular basis of its mechanism of inhibition}},
author = {Julien Bauer and Priscillia Lagoutte and Jonathan Vaneyck and Valeria Calvaresi and Emmanuel Bettler and Mireille Dumoulin and Catherine Moali and Loic Carrique and Sandrine Vadon-Le Goff},
howpublished = {HAL},
year = {2026},
month = sep,
doi = {10.64898/2026.09.22.752281},
url = {https://hal.science/hal-05761992v1},
note = {CC BY 4.0},
}
RIS
TY - UNPB
TI - Structure of PCPE-2 in complex with the BMP-1 metalloprotease reveals the molecular basis of its mechanism of inhibition
AU - Julien Bauer
AU - Priscillia Lagoutte
AU - Jonathan Vaneyck
AU - Valeria Calvaresi
AU - Emmanuel Bettler
AU - Mireille Dumoulin
AU - Catherine Moali
AU - Loic Carrique
AU - Sandrine Vadon-Le Goff
PY - 2026
DA - 2026/09/22
PB - HAL
DO - 10.64898/2026.09.22.752281
UR - https://hal.science/hal-05761992v1
AB - PCPE-2 (procollagen C-proteinase enhancer-2) is an extracellular glycoprotein playing dual functions in the regulation of BMP-1/tolloid-like proteinases. Like its homologue PCPE-1, PCPE-2 can enhance the proteolytic maturation of fibrillar procollagens, but it also acts as a potent and specific inhibitor of BMP-1 through formation of a high-affinity complex with the protease. Here, we investigated the molecular basis of this inhibitory interaction using complementary biochemical, biophysical and structural approaches. We show that the two CUB domains of PCPE-2 must be covalently linked for efficient BMP-1 binding and inhibition, consistent with cooperative engagement of the protease. Cryo-electron microscopy combined with density-guided structural modelling and hydrogen/deuterium-exchange mass spectrometry supports a bipartite interaction complex in which the CUB1 domain of PCPE-2 engages the catalytic domain of BMP-1, while the CUB2 domains of both proteins interact together. The interaction involves the calcium-binding surfaces of the PCPE-2 CUB domains that also participate in procollagen recognition, providing a structural framework for understanding the mutually exclusive interactions of PCPE-2 with BMP-1 and procollagen. Allosteric inhibition is supported by the binding of PCPE-2 CUB1 opposite to the active site cleft, leading to the shielding of the residues surrounding the S1-prime pocket, as observed by HDX-MS. Together, these findings define the architecture of the inhibitory PCPE-2/BMP-1 complex and provide the molecular basis for understanding the distinct regulatory activities of the two procollagen C-proteinase enhancers.
ER -