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Efrat Kessler - One of the best experts on this subject based on the ideXlab platform.

  • asCorbiC aCid promotes ProCollagen C Proteinase enhanCer 1 expression seCretion and Cell membrane loCalization
    Anatomical Record-advances in Integrative Anatomy and Evolutionary Biology, 2020
    Co-Authors: Ofra Gohar, Tali Weiss, Eitan Wineman, Efrat Kessler
    Abstract:

    : Removal of the C-propeptide from fibrillar ProCollagens is essential for Collagen fibril assembly. The reaCtion is Catalyzed by bone morphogenetiC protein-1/tolloid-like Proteinases and is aCCelerated by ProCollagen C-Proteinase enhanCer 1 (PCPE-1), an extraCellular matrix glyCoprotein that binds to the ProCollagen C-propeptide and its expression overlaps that of Collagen. AsCorbiC aCid (AsC) is vital for Collagen hydroxylation, folding, and seCretion. It also inCreases Collagen gene expression. The role of AsC as a regulator of PCPE-1 expression is debatable. To shed further light on this matter, herein, we studied the effeCts of AsC on PCPE-1 expression, seCretion, and Cellular loCalization in Rat2 and/or mouse 3T3 fibroblasts. AsC inCreased PCPE-1 expression at the translational and transCriptional levels about two-fold. It also inCreased the rate of PCPE-1 seCretion approximately six-fold. Endogenous PCPE-1 was found to be Cell assoCiated, and AsC inCreased the amount of PCPE-1 on the Cell surfaCe. In the absenCe of PCPE-1 hydroxylation, we propose that the dependenCe of PCPE-1 seCretion on AsC may be related to its role in ProCollagen seCretion. LoCalization of PCPE-1 to the Cell membrane favors the Cell-surfaCe as a physiologiCal site of PCPE-1 aCtion. Anat ReC, 2019. © 2019 Wiley PeriodiCals, InC.

  • analysis of ProCollagen C Proteinase enhanCer 1 glyCosaminoglyCan binding sites and of the potential role of CalCium ions in the interaCtion
    International Journal of Molecular Sciences, 2019
    Co-Authors: Jan Potthoff, Efrat Kessler, Sylvie Ricardblum, Krzysztof K Bojarski, Gergely Kohut, Agnieszka G Lipska, Adam Liwo, Sergey A Samsonov
    Abstract:

    In this study, we CharaCterize the interaCtions between the extraCellular matrix protein, ProCollagen C-Proteinase enhanCer-1 (PCPE-1), and glyCosaminoglyCans (GAGs), whiCh are linear anioniC periodiC polysaCCharides. We applied moleCular modeling approaChes to build a struCtural model of full-length PCPE-1, whiCh is not experimentally available, to prediCt GAG binding poses for various GAG lengths, types and sulfation patterns, and to determine the effeCt of CalCium ions on the binding. The Computational data are analyzed and disCussed in the Context of the experimental results previously obtained using surfaCe plasmon resonanCe binding assays. We also provide experimental data on PCPE-1/GAG interaCtions obtained using inhibition assays with GAG oligosaCCharides ranging from disaCCharides to oCtadeCasaCCharides. Our results prediCt the loCalization of GAG-binding sites at the amino aCid residue level onto PCPE-1 and is the first attempt to desCribe the effeCts of ions on protein-GAG binding using modeling approaChes. In addition, this study allows us to get deeper insights into the in siliCo methodology Challenges and limitations when applied to GAG-protein interaCtions.

  • ProCollagen C Proteinase enhanCer 1 pCpe 1 in liver fibrosis
    Methods of Molecular Biology, 2019
    Co-Authors: Efrat Kessler, Eyal Hassoun
    Abstract:

    : Fibrosis is CharaCterized by exCessive deposition of Collagen and additional extraCellular matrix (ECM) Components in response to ChroniC injuries. Liver fibrosis often results from ChroniC hepatitis C virus infeCtion and alCohol abuse that Can deteriorate to Cirrhosis and liver failure. Current noninvasive diagnostiC methods of liver fibrosis are limited in their ability to deteCt and differentiate between early and intermediate stages of fibrosis. New biomarkers of fibrosis that refleCt ECM turnover are therefore badly needed. ProCollagen C-Proteinase enhanCer 1 (PCPE-1), a ConneCtive tissue glyCoprotein that funCtions as a positive regulator of C-terminal ProCollagen proCessing and subsequent Collagen fibril assembly, is a promising Candidate. Its tissue distribution and expression profile overlap those of Collagen, and its expression in fibrosis is upregulated in parallel to the inCrease in Collagen expression. The potential of PCPE-1 as a biomarker of liver fibrosis was reCently established using a CCl4 mouse model of liver fibrosis by showing that the inCrease in Collagen and PCPE-1 Content in the fibrotiC mouse liver was refleCted by elevated plasma levels of PCPE-1. This was aChieved using a newly developed highly sensitive, speCifiC, aCCurate, and reproduCible ELISA for mouse PCPE-1, whiCh is based on CommerCially available antibodies and is offered as a new researCh tool in the field. A similar ELISA test was developed for human PCPE-1, and preliminary results with plasma from liver fibrosis patients revealed inCreased plasma ConCentrations of PCPE-1 in some patients. The protoCols of both ELISA tests are outlined herein in great detail to permit their appliCation by any laboratory with similar interests.

  • data Comparing the plasma levels of ProCollagen C Proteinase enhanCer 1 pCpe 1 in healthy individuals and liver fibrosis patients
    Data in Brief, 2017
    Co-Authors: Eyal Hassoun, Mary Safrin, Eitan Wineman, Peretz Weiss, Efrat Kessler
    Abstract:

    This artiCle provides a protoCol for determination of human ProCollagen C-Proteinase enhanCer 1 (PCPE-1) ConCentrations by ELISA. The inter-assay and intra-assay CoeffiCients of variability are given and so are the average plasma ConCentrations of PCPE-1 in healthy (Control) individuals and liver fibrosis patients.

  • data Comparing the kinetiCs of ProCollagen type i proCessing by bone morphogenetiC protein 1 bmp 1 with and without ProCollagen C Proteinase enhanCer 1 pCpe 1
    Data in Brief, 2016
    Co-Authors: Laura Moschcovich, Efrat Kessler
    Abstract:

    This artiCle provides kinetiC Constants for C-terminal proCessing of ProCollagen type I by bone morphogenetiC protein 1 (BMP-1; the major ProCollagen C-Proteinase), a reaCtion stimulated by the ConneCtive tissue glyCoprotein ProCollagen C-Proteinase enhanCer 1 (PCPE-1). Reported are Km, Vmax, KCat and KCat/Km (CatalytiC CoeffiCient) values for BMP-1 alone, BMP-1 with intaCt PCPE-1, BMP-1 with the CUB (Complement C1r/C1s, Uegf, BMP-1) domains fragment of PCPE-1 as well as its NTR (netrin-like) domain.

Keith A M Walker - One of the best experts on this subject based on the ideXlab platform.

Sharon M Dankwardt - One of the best experts on this subject based on the ideXlab platform.

David J S Hulmes - One of the best experts on this subject based on the ideXlab platform.

  • BMP-1/tolloid-like Proteinases synChronize matrix assembly with growth faCtor aCtivation to promote morphogenesis and tissue remodeling.
    Matrix biology : journal of the International Society for Matrix Biology, 2015
    Co-Authors: Sandrine Vadon-le Goff, David J S Hulmes, Catherine Moali
    Abstract:

    Bone morphogenetiC protein-1 (BMP-1)/tolloid-like Proteinases, here Called BTPs, inClude the proteases originally identified for their roles in the C-terminal maturation of fibrillar ProCollagens ("ProCollagen C-Proteinase"). Though numerous other substrates have sinCe been disCovered, the BTPs remain the main proteases involved in extraCellular matrix assembly with little or no impliCation in matrix degradation. During the same period however, the BTPs have also beCome established as important proteases in the aCtivation of growth faCtors, inCluding TGF-β1, BMP-2/-4, GDF-8/-11 and IGFs, as well as the release of anti-angiogeniC fragments from parent proteins. The BTPs are therefore key players in many pathophysiologiCal proCesses suCh as morphogenesis, tissue repair and tumor progression. This mini-review summarizes our Current knowledge of the funCtions of BTPs, their substrates and unusual meChanisms of regulation, and disCusses their potential as new targets for future therapies.

  • upregulation of bone morphogenetiC protein 1 mammalian tolloid and ProCollagen C Proteinase enhanCer 1 in Corneal sCarring
    Investigative Ophthalmology & Visual Science, 2014
    Co-Authors: F Malecaze, David J S Hulmes, Catherine Moali, Dawiyat Massoudi, P Fournie, Cyrielle Tricoire, Myriam Cassagne, Marilyne Malbouyres, Stephane Galiacy
    Abstract:

    Purpose: To CharaCterize the expression of the bone morphogenetiC protein-1 (BMP-1)/tolloid-like Proteinases (ColleCtively Called BTPs), whiCh inClude BMP-1, mammalian tolloid (mTLD), and mammalian tolloid-like 1 (mTLL-1) and 2 (mTLL-2), as well as the assoCiated proteins ProCollagen C-Proteinase enhanCers (PCPE-1 and -2), in Corneal sCarring. Methods: Using a mouse full-thiCkness Corneal exCision model, wound healing was followed for up to 28 days by transmission eleCtron miCrosCopy, immunohistology (BMP-1/mTLD and PCPE-1), and quantitative PCR (Q-PCR: Collagen III, BMP-1/mTLD, mTLL-1, mTLL-2, PCPE-1, PCPE-2). Bone morphogenetiC protein-1/mTLD and PCPE-1 were also immunoloCalized in Cases of human Corneal sCarring following injuries. Results: In the mouse model, throughout the follow-up period, there was a large inCrease in Collagen III mRNA expression in the stroma. By transmission eleCtron miCrosCopy, there was marked Cellular infiltration into the wound as well as disorganization of Collagen fibrils, but no signifiCant differenCe in fibril diameter. In Control Corneas, by Q-PCR, BMP-1/mTLD showed the highest expression, Compared to low levels of mTLL-1 and undeteCtable levels of mTLL-2, in both epithelium and stroma. Following wounding, both BMP-1/mTLD and PCPE-1 mRNA and protein inCreased, while PCPE-2 mRNA deCreased. Finally, by immunofluoresCenCe, BMP-1/mTLD and PCPE-1 were strongly expressed in the sCar region in both mouse and human Corneas. ConClusions: Bone morphogenetiC protein-1/mTLD and PCPE-1 are upregulated in Corneal sCars. Both proteins may therefore Contribute to the proCess of Corneal sCarring.

  • ProCollagen C Proteinase enhanCer grasps the stalk of the C propeptide trimer to boost Collagen preCursor maturation
    Proceedings of the National Academy of Sciences of the United States of America, 2013
    Co-Authors: Jeanmarie Bourhis, Sandrine Vadonle Goff, Natacha Mariano, Catherine Moali, Daniel Kronenberg, Hassnae Afrache, Nicole Thielens, David J S Hulmes
    Abstract:

    Tight regulation of Collagen fibril deposition in the extraCellular matrix is essential for normal tissue homeostasis and repair, defeCts in whiCh are assoCiated with several degenerative or fibrotiC disorders. A key regulatory step in Collagen fibril assembly is the C-terminal proteolytiC proCessing of soluble ProCollagen preCursors. This step, Carried out mainly by bone morphogenetiC protein-1/tolloid-like Proteinases, is itself subjeCt to regulation by ProCollagen C-Proteinase enhanCer proteins (PCPEs) whiCh Can dramatiCally inCrease bone morphogenetiC protein-1/tolloid-like Proteinase aCtivity, in a substrate-speCifiC manner. Although it is known that this enhanCing aCtivity requires binding of PCPE to the ProCollagen C-propeptide trimer, identifiCation of the preCise binding site has so far remained elusive. Here, use of small-angle X-ray sCattering provides struCtural data on this protein Complex indiCating that PCPE binds to the stalk region of the ProCollagen C-propeptide trimer, where the three polypeptide Chains assoCiate together, at the junCtion with the base region. This is supported by site-direCted mutagenesis, whiCh identifies two highly Conserved, surfaCe-exposed lysine residues in this region of the trimer that are essential for binding, thus revealing struCtural parallels with the interaCtions of Complement C1r/C1s, Uegf, BMP-1 (CUB) domain-Containing proteins in diverse biologiCal systems suCh as Complement aCtivation, reCeptor signaling, and transport. Together with detailed kinetiCs and interaCtion analysis, these results provide insights into the meChanism of aCtion of PCPEs and suggest Clear strategies for the development of novel antifibrotiC therapies.

  • ProCollagen C Proteinase enhanCer stimulates ProCollagen proCessing by binding to the C propeptide region only
    Journal of Biological Chemistry, 2011
    Co-Authors: Sandrine Vadonle Goff, David J S Hulmes, Walter Stocker, Daniel Kronenberg, Jeanmarie Bourhis, Cecile Bijakowski, Nicolas Raynal, Florence Ruggiero, Richard W Farndale, Catherine Moali
    Abstract:

    Bone morphogenetiC protein-1 (BMP-1) and the tolloid-like metalloProteinases Control several aspeCts of embryoniC development and tissue repair. Unlike other Proteinases whose aCtivities are regulated mainly by endogenous inhibitors, regulation of BMP-1/tolloid-like Proteinases relies mostly on proteins that stimulate aCtivity. Among these, ProCollagen C-Proteinase enhanCers (PCPEs) markedly inCrease BMP-1/tolloid-like Proteinase aCtivity on fibrillar ProCollagens, in a substrate-speCifiC manner. Here, we performed a detailed quantitative study of the binding of PCPE-1 and of its minimal aCtive fragment (CUB1-CUB2) to three regions of the ProCollagen III moleCule: the triple helix, the C-telopeptide, and the C-propeptide. Contrary to results desCribed elsewhere, we found the PCPE-1-binding sites to be loCated exClusively in the C-propeptide region. In addition, binding and enhanCing aCtivities were found to be independent of the glyCosylation state of the C-propeptide. These data exClude previously proposed meChanisms for the aCtion of PCPEs and also suggest new meChanisms to explain how these proteins Can stimulate BMP-1/tolloid-like Proteinases by up to 20-fold.

  • ProCessing of ProCollagen III by Meprins: New Players in ExtraCellular Matrix Assembly?
    Journal of Investigative Dermatology, 2010
    Co-Authors: Daniel Kronenberg, David J S Hulmes, Sandrine Vadonle Goff, Catherine Moali, Walter Stocker, Bernd Cem Bruns, Erwin E. Sterchi, Heiko Traupe, Markus Böhm, Christoph Becker-pauly
    Abstract:

    Meprins α and β, a subgroup of zinC metalloProteinases belonging to the astaCin family, are known to Cleave Components of the extraCellular matrix, either during physiologiCal remodeling or in pathologiCal situations. In this study we present a new role for meprins in matrix assembly, namely the proteolytiC proCessing of ProCollagens. Both meprins α and β release the N- and C-propeptides from ProCollagen III, with suCh proCessing events being CritiCal steps in Collagen fibril formation. In addition, both meprins Cleave ProCollagen III at exaCtly the same site as the ProCollagen C-Proteinases, inCluding bone morphogenetiC protein-1 (BMP-1) and other members of the tolloid Proteinase family. Indeed, Cleavage of ProCollagen III by meprins is more effiCient than by BMP-1. In addition, unlike BMP-1, whose aCtivity is stimulated by ProCollagen C-Proteinase enhanCer proteins (PCPEs), the aCtivity of meprins on ProCollagen III is diminished by PCPE-1. Finally, following our earlier observations of meprin expression by human epidermal keratinoCytes, meprin α is also shown to be expressed by human dermal fibroblasts. In the dermis of fibrotiC skin (keloids), expression of meprin α inCreases and meprin β begins to be deteCted. Our study suggests that meprins Could be important players in several remodeling proCesses involving Collagen fiber deposition.

Catherine Moali - One of the best experts on this subject based on the ideXlab platform.

  • struCtural basis for the aCCeleration of ProCollagen proCessing by ProCollagen C Proteinase enhanCer 1
    Structure, 2018
    Co-Authors: David Pulido, Urvashi Sharma, Sandrine Vadonle Goff, Sadafahmahni Hussain, Sarah Cordes, Natacha Mariano, Emmanuel Bettler, Catherine Moali, Nushin Aghajari, Erhard Hohenester
    Abstract:

    Summary 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.

  • fonCtions divergentes des ProCollagen C Proteinase enhanCers pCpe 1 et pCpe 2 dans la CiCatrisation Cutanee
    Annales De Dermatologie Et De Venereologie, 2016
    Co-Authors: Sandrine Vadonle Goff, Agnes Tessier, Leena Brucknertuderman, Alexander Nystrom, Catherine Moali
    Abstract:

    IntroduCtion Au Cours de la CiCatrisation Cutanee, la balanCe entre synthese et degradation des Collagenes joue un role CruCial dans la restauration et le maintien de l’integrite struCturale et meCanique de la peau. De fait, diverses pathologies Cutanees (plaies Chroniques, CiCatriCes hypertrophiques et Cheloides) affeCtant la sante et la qualite de vie des patients sont Causees par des defauts de fibrillogenese. Les Collagenes sont synthetises et seCretes sous forme de preCurseurs solubles par les fibroblastes. Dans l’espaCe extraCellulaire, leur extremite C-terminale est alors Clivee par des proteases, de la famille BMP-1/Tolloid-like (BTPs), Ce qui permet la formation de fibres de Collagene. Ce Clivage proteolytique est stimule d’un faCteur dix par une glyCoproteine, « ProCollagen C-Proteinase EnhanCer-1 » (PCPE-1), Connue pour etre impliquee dans differents Contextes de reparation tissulaire. ReCemment, une deuxieme isoforme de PCPE a ete deCrite : PCPE-2 serait Capable de stimuler la maturation des ProCollagenes in vitro et jouerait un role essentiel dans la synthese du Collagene Chez la souris dans un modele d’hypertrophie Cardiaque. Ainsi, l’objeCtif de Ce travail est d’etudier les roles de PCPE-1 et PCPE-2 dans la CiCatrisation de la peau. Materiel et methodes Pour Comprendre le role de PCPE-1 et PCPE-2 dans la CiCatrisation, l’expression et la distribution des PCPE et des BTP ont ete etudiees par qRT-PCR, western blot et immunofluoresCenCe dans des modeles Cellulaire (fibroblastes et keratinoCytes) et tissulaire (modele murin de CiCatrisation). En parallele, un systeme d’expression de PCPE-2 a ete mis en plaCe afin de produire la proteine humaine reCombinante dans le but d’evaluer son aCtivite sur les ProCollagenes. Resultats Les BTP sont exprimees a la fois par les fibroblastes et les keratinoCytes ; leur expression augmente pendant la CiCatrisation dans la peau de souris. De faCon interessante, les deux isoformes de PCPE ne sont pas exprimees par le meme type Cellulaire dans la peau : PCPE-1 est fortement exprimee par les fibroblastes et son expression augmente de faCon signifiCative apres une lesion Cutanee. A l’inverse, PCPE-2 n’est pas retrouvee dans la peau non lesee mais est fortement exprimee par les neutrophiles dans les premieres phases de CiCatrisation Chez la souris. Les premiers tests d’aCtivite realises semblent demontrer que la proteine PCPE-2 purifiee a beauCoup moins d’effet que PCPE-1 sur la maturation des Collagenes. DisCussion Ces travaux suggerent que PCPE-1 et PCPE-2 auraient des roles distinCts dans la CiCatrisation Cutanee. Alors que PCPE-1 est un aCteur majeur de la fibrillogenese dans la peau et pendant la CiCatrisation, l’expression de PCPE-2 par des Cellules immunitaires suggere une fonCtion alternative de Cette isoforme. Notre objeCtif est desormais de Comprendre le role de PCPE-2 exprimee par les neutrophiles pendant la CiCatrisation.

  • BMP-1/tolloid-like Proteinases synChronize matrix assembly with growth faCtor aCtivation to promote morphogenesis and tissue remodeling.
    Matrix biology : journal of the International Society for Matrix Biology, 2015
    Co-Authors: Sandrine Vadon-le Goff, David J S Hulmes, Catherine Moali
    Abstract:

    Bone morphogenetiC protein-1 (BMP-1)/tolloid-like Proteinases, here Called BTPs, inClude the proteases originally identified for their roles in the C-terminal maturation of fibrillar ProCollagens ("ProCollagen C-Proteinase"). Though numerous other substrates have sinCe been disCovered, the BTPs remain the main proteases involved in extraCellular matrix assembly with little or no impliCation in matrix degradation. During the same period however, the BTPs have also beCome established as important proteases in the aCtivation of growth faCtors, inCluding TGF-β1, BMP-2/-4, GDF-8/-11 and IGFs, as well as the release of anti-angiogeniC fragments from parent proteins. The BTPs are therefore key players in many pathophysiologiCal proCesses suCh as morphogenesis, tissue repair and tumor progression. This mini-review summarizes our Current knowledge of the funCtions of BTPs, their substrates and unusual meChanisms of regulation, and disCusses their potential as new targets for future therapies.

  • upregulation of bone morphogenetiC protein 1 mammalian tolloid and ProCollagen C Proteinase enhanCer 1 in Corneal sCarring
    Investigative Ophthalmology & Visual Science, 2014
    Co-Authors: F Malecaze, David J S Hulmes, Catherine Moali, Dawiyat Massoudi, P Fournie, Cyrielle Tricoire, Myriam Cassagne, Marilyne Malbouyres, Stephane Galiacy
    Abstract:

    Purpose: To CharaCterize the expression of the bone morphogenetiC protein-1 (BMP-1)/tolloid-like Proteinases (ColleCtively Called BTPs), whiCh inClude BMP-1, mammalian tolloid (mTLD), and mammalian tolloid-like 1 (mTLL-1) and 2 (mTLL-2), as well as the assoCiated proteins ProCollagen C-Proteinase enhanCers (PCPE-1 and -2), in Corneal sCarring. Methods: Using a mouse full-thiCkness Corneal exCision model, wound healing was followed for up to 28 days by transmission eleCtron miCrosCopy, immunohistology (BMP-1/mTLD and PCPE-1), and quantitative PCR (Q-PCR: Collagen III, BMP-1/mTLD, mTLL-1, mTLL-2, PCPE-1, PCPE-2). Bone morphogenetiC protein-1/mTLD and PCPE-1 were also immunoloCalized in Cases of human Corneal sCarring following injuries. Results: In the mouse model, throughout the follow-up period, there was a large inCrease in Collagen III mRNA expression in the stroma. By transmission eleCtron miCrosCopy, there was marked Cellular infiltration into the wound as well as disorganization of Collagen fibrils, but no signifiCant differenCe in fibril diameter. In Control Corneas, by Q-PCR, BMP-1/mTLD showed the highest expression, Compared to low levels of mTLL-1 and undeteCtable levels of mTLL-2, in both epithelium and stroma. Following wounding, both BMP-1/mTLD and PCPE-1 mRNA and protein inCreased, while PCPE-2 mRNA deCreased. Finally, by immunofluoresCenCe, BMP-1/mTLD and PCPE-1 were strongly expressed in the sCar region in both mouse and human Corneas. ConClusions: Bone morphogenetiC protein-1/mTLD and PCPE-1 are upregulated in Corneal sCars. Both proteins may therefore Contribute to the proCess of Corneal sCarring.

  • ProCollagen C Proteinase enhanCer grasps the stalk of the C propeptide trimer to boost Collagen preCursor maturation
    Proceedings of the National Academy of Sciences of the United States of America, 2013
    Co-Authors: Jeanmarie Bourhis, Sandrine Vadonle Goff, Natacha Mariano, Catherine Moali, Daniel Kronenberg, Hassnae Afrache, Nicole Thielens, David J S Hulmes
    Abstract:

    Tight regulation of Collagen fibril deposition in the extraCellular matrix is essential for normal tissue homeostasis and repair, defeCts in whiCh are assoCiated with several degenerative or fibrotiC disorders. A key regulatory step in Collagen fibril assembly is the C-terminal proteolytiC proCessing of soluble ProCollagen preCursors. This step, Carried out mainly by bone morphogenetiC protein-1/tolloid-like Proteinases, is itself subjeCt to regulation by ProCollagen C-Proteinase enhanCer proteins (PCPEs) whiCh Can dramatiCally inCrease bone morphogenetiC protein-1/tolloid-like Proteinase aCtivity, in a substrate-speCifiC manner. Although it is known that this enhanCing aCtivity requires binding of PCPE to the ProCollagen C-propeptide trimer, identifiCation of the preCise binding site has so far remained elusive. Here, use of small-angle X-ray sCattering provides struCtural data on this protein Complex indiCating that PCPE binds to the stalk region of the ProCollagen C-propeptide trimer, where the three polypeptide Chains assoCiate together, at the junCtion with the base region. This is supported by site-direCted mutagenesis, whiCh identifies two highly Conserved, surfaCe-exposed lysine residues in this region of the trimer that are essential for binding, thus revealing struCtural parallels with the interaCtions of Complement C1r/C1s, Uegf, BMP-1 (CUB) domain-Containing proteins in diverse biologiCal systems suCh as Complement aCtivation, reCeptor signaling, and transport. Together with detailed kinetiCs and interaCtion analysis, these results provide insights into the meChanism of aCtion of PCPEs and suggest Clear strategies for the development of novel antifibrotiC therapies.