Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
Dynamics of the secreted frizzled related protein Sizzled and potential implications for binding to bone morphogenetic protein-1 (BMP-1).
Sharma U
,
Vadon-Le Goff S
,
Harlos K
,
Zhao Y
,
Mariano N
,
Bijakowski C
,
Bourhis JM
,
Moali C
,
Hulmes DJS
,
Aghajari N
.
???displayArticle.abstract??? Sizzled (Szl) is both a secreted frizzled related protein (sFRP) and a naturally occurring inhibitor of the zinc metalloproteinase bone morphogenetic protein-1 (BMP-1), a key regulator of extracellular matrix assembly and growth factor activation. Here we present a new crystal structure for Szl which differs from that previously reported by a large scale (90°) hinge rotation between its cysteine-rich and netrin-like domains. We also present results of a molecular docking analysis showing interactions likely to be involved in the inhibition of BMP-1 activity by Szl. When compared with known structures of BMP-1 in complex with small molecule inhibitors, this reveals features that may be helpful in the design of new inhibitors to prevent the excessive accumulation of extracellular matrix that is the hallmark of fibrotic diseases.
Figure 1. Low resolution envelope of Szl determined by SAXS with superimposed crystal structures of 5XGP and the new structure reported here (PDB-ID 7EL5). (a) SAXS envelope only shown in side view (top), top view (middle) and side view rotated 90° about the vertical axis (bottom). (b) With superimposed full length ribbon diagram of the structure reported here (in green and including modelled inter-domain linker and N- and C-terminal ends). (c) As B but for 5XGP (in blue). (d) Both structures superimposed and aligned using their N-terminal CRD domains.
Figure 2. Overall fold and topology diagram of the new crystal structure of Szl. This structure (PDB-ID 7EL5), shows α-helices in orange (CRD) and salmon (NTR), β-sheets in purple (CRD) and teal (NTR) and unstructured areas and loops in green. Also shown are positions of S2′, S1′, S1 and S2 subsites in Szl referred to in the text, as well as positions of corresponding residues in Szl and interaction partners in BMP-1 (the latter in the blue box). The positions of subsites are indicated by yellow stars on the ribbon presentation.
Figure 3. Overlay of the two crystal structures of Szl. (a) Side views of the new structure described here “7EL5” (green) and 5XGP (blue) aligned using their NTR domains and shown as ribbon presentations. (b) Top view showing the relative rotation of the CRD domains by about 90° as indicated by the dotted lines and marker residues shown in orange (new structure) and magenta (5XGP). Disulphide bridges are depicted in yellow with the inter-domain bond labelled “SS”.
Adams,
PHENIX: a comprehensive Python-based system for macromolecular structure solution.
2010, Pubmed
Adams,
PHENIX: a comprehensive Python-based system for macromolecular structure solution.
2010,
Pubmed
Afonine,
Towards automated crystallographic structure refinement with phenix.refine.
2012,
Pubmed
Aricescu,
A time- and cost-efficient system for high-level protein production in mammalian cells.
2006,
Pubmed
Bailey,
Succinyl hydroxamates as potent and selective non-peptidic inhibitors of procollagen C-proteinase: design, synthesis, and evaluation as topically applied, dermal anti-scarring agents.
2008,
Pubmed
Ballut,
Active site coupling in Plasmodium falciparum GMP synthetase is triggered by domain rotation.
2015,
Pubmed
Bernstein,
Synergistic effects of substrate-induced conformational changes in phosphoglycerate kinase activation.
1997,
Pubmed
Bijakowski,
Sizzled is unique among secreted frizzled-related proteins for its ability to specifically inhibit bone morphogenetic protein-1 (BMP-1)/tolloid-like proteinases.
2012,
Pubmed
,
Xenbase
Bovolenta,
Beyond Wnt inhibition: new functions of secreted Frizzled-related proteins in development and disease.
2008,
Pubmed
Bu,
The crystal structure of full-length Sizzled from Xenopus laevis yields insights into Wnt-antagonistic function of secreted Frizzled-related proteins.
2017,
Pubmed
,
Xenbase
Chen,
MolProbity: all-atom structure validation for macromolecular crystallography.
2010,
Pubmed
Collavin,
The secreted Frizzled-related protein Sizzled functions as a negative feedback regulator of extreme ventral mesoderm.
2003,
Pubmed
,
Xenbase
Dann,
Insights into Wnt binding and signalling from the structures of two Frizzled cysteine-rich domains.
2001,
Pubmed
,
Xenbase
De Robertis,
Generation of animal form by the Chordin/Tolloid/BMP gradient: 100 years after D'Arcy Thompson.
2017,
Pubmed
,
Xenbase
Dive,
Inhibition of zinc metallopeptidases in cardiovascular disease--from unity to trinity, or duality?
2009,
Pubmed
Eckhard,
The crystal structure of a 250-kDa heterotetrameric particle explains inhibition of sheddase meprin β by endogenous fetuin-B.
2021,
Pubmed
Emekli,
HingeProt: automated prediction of hinges in protein structures.
2008,
Pubmed
Emsley,
Coot: model-building tools for molecular graphics.
2004,
Pubmed
Fish,
Potent and selective nonpeptidic inhibitors of procollagen C-proteinase.
2007,
Pubmed
Franke,
DAMMIF, a program for rapid ab-initio shape determination in small-angle scattering.
2009,
Pubmed
Franke,
ATSAS 2.8: a comprehensive data analysis suite for small-angle scattering from macromolecular solutions.
2017,
Pubmed
Garrigue-Antar,
Identification of amino acid residues in bone morphogenetic protein-1 important for procollagen C-proteinase activity.
2001,
Pubmed
Guevara,
Proenzyme structure and activation of astacin metallopeptidase.
2010,
Pubmed
Guttman,
All-atom ensemble modeling to analyze small-angle x-ray scattering of glycosylated proteins.
2013,
Pubmed
He,
Exogenously administered secreted frizzled related protein 2 (Sfrp2) reduces fibrosis and improves cardiac function in a rat model of myocardial infarction.
2010,
Pubmed
,
Xenbase
Janda,
Structural basis of Wnt recognition by Frizzled.
2012,
Pubmed
,
Xenbase
Jumper,
Highly accurate protein structure prediction with AlphaFold.
2021,
Pubmed
Kabsch,
XDS.
2010,
Pubmed
Kallander,
Reverse Hydroxamate Inhibitors of Bone Morphogenetic Protein 1.
2018,
Pubmed
Kawano,
Secreted antagonists of the Wnt signalling pathway.
2003,
Pubmed
,
Xenbase
Kobayashi,
Secreted Frizzled-related protein 2 is a procollagen C proteinase enhancer with a role in fibrosis associated with myocardial infarction.
2009,
Pubmed
,
Xenbase
Kozakov,
PIPER: an FFT-based protein docking program with pairwise potentials.
2006,
Pubmed
Kozakov,
The ClusPro web server for protein-protein docking.
2017,
Pubmed
Laskowski,
PDBsum: Structural summaries of PDB entries.
2018,
Pubmed
Lee,
Embryonic dorsal-ventral signaling: secreted frizzled-related proteins as inhibitors of tolloid proteinases.
2006,
Pubmed
,
Xenbase
Mac Sweeney,
Structural basis for the substrate specificity of bone morphogenetic protein 1/tolloid-like metalloproteases.
2008,
Pubmed
Martyn,
The ventralized ogon mutant phenotype is caused by a mutation in the zebrafish homologue of Sizzled, a secreted Frizzled-related protein.
2003,
Pubmed
Mii,
Secreted Wnt "inhibitors" are not just inhibitors: regulation of extracellular Wnt by secreted Frizzled-related proteins.
2011,
Pubmed
Muraoka,
Sizzled controls dorso-ventral polarity by repressing cleavage of the Chordin protein.
2006,
Pubmed
Murshudov,
REFMAC5 for the refinement of macromolecular crystal structures.
2011,
Pubmed
Orellana,
Large-Scale Conformational Changes and Protein Function: Breaking the in silico Barrier.
2019,
Pubmed
Pettersen,
UCSF Chimera--a visualization system for exploratory research and analysis.
2004,
Pubmed
Pijning,
Flexibility of truncated and full-length glucansucrase GTF180 enzymes from Lactobacillus reuteri 180.
2014,
Pubmed
Ploper,
Dorsal-ventral patterning: Crescent is a dorsally secreted Frizzled-related protein that competitively inhibits Tolloid proteases.
2011,
Pubmed
,
Xenbase
Pulido,
Structural Basis for the Acceleration of Procollagen Processing by Procollagen C-Proteinase Enhancer-1.
2018,
Pubmed
Rawlings,
The MEROPS database of proteolytic enzymes, their substrates and inhibitors in 2017 and a comparison with peptidases in the PANTHER database.
2018,
Pubmed
Sali,
Comparative protein modelling by satisfaction of spatial restraints.
1993,
Pubmed
Schechter,
On the size of the active site in proteases. I. Papain.
1967,
Pubmed
Schiering,
Structure of neprilysin in complex with the active metabolite of sacubitril.
2016,
Pubmed
Scott,
Homologues of Twisted gastrulation are extracellular cofactors in antagonism of BMP signalling.
2001,
Pubmed
,
Xenbase
Sun,
The expression of twisted gastrulation in postnatal mouse brain and functional implications.
2010,
Pubmed
Talantikite,
Inhibitors of BMP-1/tolloid-like proteinases: efficacy, selectivity and cellular toxicity.
2018,
Pubmed
Tina,
PIC: Protein Interactions Calculator.
2007,
Pubmed
Turtle,
Design and synthesis of procollagen C-proteinase inhibitors.
2012,
Pubmed
Vadon-Le Goff,
BMP-1/tolloid-like proteinases synchronize matrix assembly with growth factor activation to promote morphogenesis and tissue remodeling.
2015,
Pubmed
Vagin,
Molecular replacement with MOLREP.
2010,
Pubmed
Vajda,
New additions to the ClusPro server motivated by CAPRI.
2017,
Pubmed
Winn,
Overview of the CCP4 suite and current developments.
2011,
Pubmed
Winter,
Decision making in xia2.
2013,
Pubmed
Yabe,
Ogon/Secreted Frizzled functions as a negative feedback regulator of Bmp signaling.
2003,
Pubmed
,
Xenbase
Zhao,
Structural insights into the inhibition of Wnt signaling by cancer antigen 5T4/Wnt-activated inhibitory factor 1.
2014,
Pubmed
Zhu,
Synergistic effect of PCPE1 and sFRP2 on the processing of procollagens via BMP1.
2019,
Pubmed
von Marschall,
Dentin sialophosphoprotein (DSPP) is cleaved into its two natural dentin matrix products by three isoforms of bone morphogenetic protein-1 (BMP1).
2010,
Pubmed
