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• W2895468049 abstract "In this issue of Structure, Pulido et al., 2018Pulido D. Sharma U. Vadon-Le Goff S. Hussain S.A. Cordes S. Mariano N. Bettler E. Moali C. Aghajari N. Hohenester E. Hulmes D.J.S. Structural Basis for the Acceleration of Procollagen Processing by Procollagen C-Proteinase Enhancer-1.Structure. 2018; 26 (this issue): 1384-1392Abstract Full Text Full Text PDF PubMed Scopus (21) Google Scholar determine the crystal structure of procollagen C-proteinase enhancer-1 (PCPE-1)/procollagen III complex and identify that PCPE-1 unwinds the stalk of the procollagen III trimer, liberating a single chain to facilitate binding and cleavage by BMP-1 proteinases for subsequent fibrillar collagen assembly. In this issue of Structure, Pulido et al., 2018Pulido D. Sharma U. Vadon-Le Goff S. Hussain S.A. Cordes S. Mariano N. Bettler E. Moali C. Aghajari N. Hohenester E. Hulmes D.J.S. Structural Basis for the Acceleration of Procollagen Processing by Procollagen C-Proteinase Enhancer-1.Structure. 2018; 26 (this issue): 1384-1392Abstract Full Text Full Text PDF PubMed Scopus (21) Google Scholar determine the crystal structure of procollagen C-proteinase enhancer-1 (PCPE-1)/procollagen III complex and identify that PCPE-1 unwinds the stalk of the procollagen III trimer, liberating a single chain to facilitate binding and cleavage by BMP-1 proteinases for subsequent fibrillar collagen assembly. Procollagen C-proteinase processes procollagens by removing the C-terminal propeptide of fibrillar procollagens to allow assembly of collagen fibrils. Procollagen C-proteinase is also known as bone morphogenetic protein-1 (BMP-1), a member of the mammalian tolloid family, a small group of zinc- and calcium-dependent proteinases. In vertebrates, BMP-1/mTLD proteinases (BTPs) are involved in the biosynthetic processing of a diverse range of extracellular matrix precursors required for laying down the extracellular matrix and normal tissue assembly. Substrates include the major and minor fibrillar procollagens, the collagen and elastin cross-linking enzyme prolysyl oxidase, cellular anchoring proteins prolaminin-5 and procollagen VII, and small leucine-rich proteoglycans (for review see Vadon-Le Goff et al., 2015Vadon-Le Goff S. Hulmes D.J. Moali C. BMP-1/tolloid-like proteinases synchronize matrix assembly with growth factor activation to promote morphogenesis and tissue remodeling.Matrix Biol. 2015; 44-46: 14-23Crossref PubMed Scopus (96) Google Scholar). BTPs are also instrumental in the release of a number of transforming growth factor (TGF)-β superfamily members from inhibitory complexes. This action modulates developmental patterning, growth of skeletal muscle, and tissue homoeostasis (Troilo et al., 2016Troilo H. Bayley C.P. Barrett A.L. Lockhart-Cairns M.P. Jowitt T.A. Baldock C. Mammalian tolloid proteinases: role in growth factor signalling.FEBS Lett. 2016; 590: 2398-2407Crossref PubMed Scopus (8) Google Scholar). The rate of procollagen cleavage by BMP-1 is specifically enhanced by two procollagen C-proteinase enhancers (PCPEs). PCPE-1 is a 55 kDa ubiquitous glycoprotein devoid of catalytic activity but able to enhance C-propeptide removal from procollagens I-III up to 20-fold (Adar et al., 1986Adar R. Kessler E. Goldberg B. Evidence for a protein that enhances the activity of type I procollagen C-proteinase.Coll. Relat. Res. 1986; 6: 267-277Crossref PubMed Scopus (54) Google Scholar). PCPE-1 is composed of three domains (Figure 1; CUB1-CUB2-NTR), but only the CUB1-CUB2 (C1C2) region is necessary for its activity (Hulmes et al., 1997Hulmes D.J. Mould A.P. Kessler E. The CUB domains of procollagen C-proteinase enhancer control collagen assembly solely by their effect on procollagen C-proteinase/bone morphogenetic protein-1.Matrix Biol. 1997; 16: 41-45Crossref PubMed Scopus (49) Google Scholar). PCPE does not enhance the processing of other BTP substrates and as excessive formation of fibrillar collagen is a major feature of fibrosis, this makes PCPE an interesting target to specifically inhibit only the procollagenase function of BMP-1. Moreover, PCPE-1 is up-regulated in hypertrophic, keloid, and corneal scars and in models of liver and cardiac fibrosis (Hassoun et al., 2016Hassoun E. Safrin M. Ziv H. Pri-Chen S. Kessler E. Procollagen C-proteinase enhancer 1 (PCPE-1) as a plasma marker of muscle and liver fibrosis in mice.PLoS One. 2016; 11: e0159606PubMed Google Scholar, Wong et al., 2014Wong V.W. You F. Januszyk M. Gurtner G.C. Kuang A.A. Transcriptional profiling of rapamycin-treated fibroblasts from hypertrophic and keloid scars.Ann. Plast. Surg. 2014; 72: 711-719Crossref PubMed Scopus (34) Google Scholar). Together these factors suggest that PCPEs have potential as new targets for anti-fibrotic therapies. In 2013, Bourhis and co-workers analyzed a complex of procollagen III (CPIII) with C1C2 of PCPE-1 using small-angle X-ray scattering (SAXS) (Bourhis et al., 2013Bourhis J.M. Vadon-Le Goff S. Afrache H. Mariano N. Kronenberg D. Thielens N. Moali C. Hulmes D.J. Procollagen C-proteinase enhancer grasps the stalk of the C-propeptide trimer to boost collagen precursor maturation.Proc. Natl. Acad. Sci. USA. 2013; 110: 6394-6399Crossref PubMed Scopus (49) Google Scholar). The structure of the CPIII trimer had previously been solved by the group of Professor David Hulmes to reveal a flower-shaped structure with three petals emerging from a central stalk (Bourhis et al., 2012Bourhis J.M. Mariano N. Zhao Y. Harlos K. Exposito J.Y. Jones E.Y. Moali C. Aghajari N. Hulmes D.J. Structural basis of fibrillar collagen trimerization and related genetic disorders.Nat. Struct. Mol. Biol. 2012; 19: 1031-1036Crossref PubMed Scopus (70) Google Scholar). Analysis of the CPIII-PCPE1 complex by SAXS showed that PCPE-1 functions via direct and tight binding to the stalk region of the collagen C-propeptide trimer. The PCPE-1 binding site is close to the BMP-1 cleavage site, and binding occurs with a stoichiometry of one PCPE-1 molecule to a procollagen trimer (Bourhis et al., 2013Bourhis J.M. Vadon-Le Goff S. Afrache H. Mariano N. Kronenberg D. Thielens N. Moali C. Hulmes D.J. Procollagen C-proteinase enhancer grasps the stalk of the C-propeptide trimer to boost collagen precursor maturation.Proc. Natl. Acad. Sci. USA. 2013; 110: 6394-6399Crossref PubMed Scopus (49) Google Scholar). This low-resolution study did not, however, explain why this stoichiometry was sufficient for the function of PCPE-1 or allow identification of the molecular interactions between CPIII and PCPE-1. In a collaboration between the Hulmes and Hohenester groups, the crystal structure of the human CPIII-C1C2 complex has been determined. While validating the SAXS model, the higher resolution of this structure has provided a more complete understanding of the mechanism of PCPE-1 enhancement of BMP-1 activity (Pulido et al., 2018Pulido D. Sharma U. Vadon-Le Goff S. Hussain S.A. Cordes S. Mariano N. Bettler E. Moali C. Aghajari N. Hohenester E. Hulmes D.J.S. Structural Basis for the Acceleration of Procollagen Processing by Procollagen C-Proteinase Enhancer-1.Structure. 2018; 26 (this issue): 1384-1392Abstract Full Text Full Text PDF PubMed Scopus (21) Google Scholar). The beautiful flower structure of CPIII is immediately apparent and consistent with the CPIII structure in the absence of PCPE-1 (root-mean-square deviation [RMSD] of 1.25 Å between 669 α carbons) (Bourhis et al., 2013Bourhis J.M. Vadon-Le Goff S. Afrache H. Mariano N. Kronenberg D. Thielens N. Moali C. Hulmes D.J. Procollagen C-proteinase enhancer grasps the stalk of the C-propeptide trimer to boost collagen precursor maturation.Proc. Natl. Acad. Sci. USA. 2013; 110: 6394-6399Crossref PubMed Scopus (49) Google Scholar). The crystal structure of the complex has also allowed the authors to identify the residues responsible for the binding between CPIII and PCPE-1. Upon inspection of the complex structure, it was immediately apparent why the stoichiometry of PCPE-1 to CPIII was 1:1, because a single PCPE-1 molecule wraps around the base of the CPIII trimer with the two CUB domains interacting with different chains of the trimer. Interestingly, the authors (Pulido et al., 2018Pulido D. Sharma U. Vadon-Le Goff S. Hussain S.A. Cordes S. Mariano N. Bettler E. Moali C. Aghajari N. Hohenester E. Hulmes D.J.S. Structural Basis for the Acceleration of Procollagen Processing by Procollagen C-Proteinase Enhancer-1.Structure. 2018; 26 (this issue): 1384-1392Abstract Full Text Full Text PDF PubMed Scopus (21) Google Scholar) noticed that in the CPIII:C1C2 complex, one of the CPIII chains from the trimer deviates from the apoCPIII structure, determined in the absence of PCPE-1. Upon inspection, it was clear that the N terminus of one chain of CPIII is pulled into the cleft between the two CUB domains of PCPE-1. PCPE-1 binding appears to unravel one chain of CPIII, exposing the BMP-1 cleavage site, which could facilitate procollagen cleavage and subsequent collagen assembly. To test this hypothesis, the authors conducted an array of structure-directed mutagenesis studies coupled with cleavage assays and surface plasmon resonance binding studies. Mutations in PCPE-1 at sites of interaction with CPIII (Arg55Ala, Arg91Ala, and Leu234Glu) were generated. In BMP-1 cleavage assays, most PCPE-1 mutations had little effect on the enhancement of BMP-1 cleavage of the mini-procollagen III substrate, with the exception of the Leu234Glu mutation, which had a decrease of 15% in BMP-1 enhancement. However, when single mutations were combined, more effects were apparent with the Arg55Ala/Leu234Glu double-mutation, reducing the enhancement of BMP-1 activity to 30%; for a triple-mutant, the enhancing activity dropped by 75%. Although the mutations altered binding between PCPE-1 and CPIII, the binding strength did not always correlate directly with the changes in PCPE-1 activity. This discrepancy can be explained by the relative importance of the location of the PCPE-1 binding site, with residues involved in binding to the CPIII stalk region having less effect on enhancing the activity than those binding to the N-terminal region. While cleavage is initially thought to occur at a single chain, it is predicted that the remaining two chains then become more susceptible to proteolysis. Subsequently, PCPE-1 may be able to re-dock with PCIII to enhance cleavage of the remaining two chains. The cleavage must occur on a per-chain basis, as it has been previously shown that the BMP-1 catalytic site is only large enough to accommodate a single procollagen chain (Mac Sweeney et al., 2008Mac Sweeney A. Gil-Parrado S. Vinzenz D. Bernardi A. Hein A. Bodendorf U. Erbel P. Logel C. Gerhartz B. Structural basis for the substrate specificity of bone morphogenetic protein 1/tolloid-like metalloproteases.J. Mol. Biol. 2008; 384: 228-239Crossref PubMed Scopus (46) Google Scholar). To illustrate this point, Hulmes and colleagues (Pulido et al., 2018Pulido D. Sharma U. Vadon-Le Goff S. Hussain S.A. Cordes S. Mariano N. Bettler E. Moali C. Aghajari N. Hohenester E. Hulmes D.J.S. Structural Basis for the Acceleration of Procollagen Processing by Procollagen C-Proteinase Enhancer-1.Structure. 2018; 26 (this issue): 1384-1392Abstract Full Text Full Text PDF PubMed Scopus (21) Google Scholar) have expanded their structure to elegantly model how BMP-1 would bind to the stalk of CPIII and how PCPE-1 directs a chain of the CPIII trimer into the BMP-1 active site. This masterful study illustrates how structural biology marries with both biochemical and biophysical assays to address fundamentally important questions in biology. Individually, these are powerful tools, but the synergy between these methods can provide even more informative data. Here the authors have shown how a combined approach can allow the structure to influence the interpretation of biochemical assays and vice versa. We apologize to colleagues working in this field whose work was not cited due to space limitations. Our work is supported by the BBSRC (Refs: BB/N015398/1 and BB/R008221/1). Structural Basis for the Acceleration of Procollagen Processing by Procollagen C-Proteinase Enhancer-1Pulido et al.StructureAugust 2, 2018In BriefCollagens 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. Full-Text PDF Open Access" @default.
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• W2895468049 title "Unraveling the Mechanism of Procollagen C-Proteinase Enhancer" @default.
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