PDBsum entry 1dy2

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Angiogenesis inhibitor PDB id
Protein chain
168 a.a. *
Waters ×45
* Residue conservation analysis
PDB id:
Name: Angiogenesis inhibitor
Title: Murine collagen alpha1(xv), endostatin domain
Structure: Collagen alpha1(xv) chain. Chain: a. Fragment: endostatin domain. Engineered: yes
Source: Mus musculus. Mouse. Organism_taxid: 10090. Expressed in: homo sapiens. Expression_system_taxid: 9606. Expression_system_cell_line: ebna-293. Expression_system_cell: embryonic kidney cell.
2.0Å     R-factor:   0.200     R-free:   0.249
Authors: D.Tisi,E.Hohenester,T.Sasaki,R.Timpl
Key ref:
T.Sasaki et al. (2000). Endostatins derived from collagens XV and XVIII differ in structural and binding properties, tissue distribution and anti-angiogenic activity. J Mol Biol, 301, 1179-1190. PubMed id: 10966814 DOI: 10.1006/jmbi.2000.3996
21-Jan-00     Release date:   21-Jan-01    
Go to PROCHECK summary

Protein chain
Pfam   ArchSchema ?
O35206  (COFA1_MOUSE) -  Collagen alpha-1(XV) chain
1367 a.a.
168 a.a.
Key:    PfamA domain  PfamB domain  Secondary structure  CATH domain

 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     extracellular matrix   1 term 
  Biological process     cell adhesion   1 term 
  Biochemical function     structural molecule activity     1 term  


DOI no: 10.1006/jmbi.2000.3996 J Mol Biol 301:1179-1190 (2000)
PubMed id: 10966814  
Endostatins derived from collagens XV and XVIII differ in structural and binding properties, tissue distribution and anti-angiogenic activity.
T.Sasaki, H.Larsson, D.Tisi, L.Claesson-Welsh, E.Hohenester, R.Timpl.
Endostatin is a fragment of the C-terminal domain NC1 of collagen XVIII that inhibits angiogenesis and tumor growth. We report the characterization of a collagen XV endostatin analogue and its parent NC1 domain, obtained by recombinant expression in mammalian cells. Both NC1 domains contain a trimerization domain, a hinge region that is more sensitive to proteolysis in collagen XVIII and the endostatin domain. Unlike endostatin-XVIII, endostatin-XV does not bind zinc or heparin, which is explained by the crystal structure of endostatin-XV. The collagen XV and XVIII fragments inhibited chorioallantoic membrane angiogenesis induced by basic fibroblast growth factor (FGF-2) or vascular endothelial growth factor (VEGF), but there are striking differences depending on which cytokine is used and whether free endostatins or NC1 domains are applied. The collagen XV and XVIII fragments showed a similar binding repertoire for extracellular matrix proteins. Differences were found in the immunohistological localization in vessel walls and basement membrane zones. Together, these data indentify endostatin-XV as an angiogenesis inhibitor, which differs from endostatin-XVIII in several important functional details.
  Selected figure(s)  
Figure 4.
Figure 4. Comparison of the binding activities of NC1-XV and endostatin-XV to fibulins and nidogens in solid-phase assays. Endostatin-XV (open symbols) and NC1-XV (filled symbols) were used as immobilized ligands. Soluble ligands were: in (a) fibulin-1 (*,*) and fibulin-2 (&,&); and in (b) nidogen-1 (!,!) and nido- gen-2 (~,~).
Figure 6.
Figure 6. Immunoblot analysis of adult mouse tissue extracts with antibodies against NC1-XV. The run was calibrated with marker proteins (left margin, in kDa) and with recombinant NC1-XV (recNC1) and endostatin-XV (recES). All samples were non- reduced.
  The above figures are reprinted by permission from Elsevier: J Mol Biol (2000, 301, 1179-1190) copyright 2000.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
20932905 J.A.Wirz, S.P.Boudko, T.F.Lerch, M.S.Chapman, and H.P.Bächinger (2011).
Crystal structure of the human collagen XV trimerization domain: a potent trimerizing unit common to multiplexin collagens.
  Matrix Biol, 30, 9.
PDB code: 3n3f
20301220 F.Wiradjaja, T.DiTommaso, and I.Smyth (2010).
Basement membranes in development and disease.
  Birth Defects Res C Embryo Today, 90, 8.  
20865019 L.Sorokin (2010).
The impact of the extracellular matrix on inflammation.
  Nat Rev Immunol, 10, 712-723.  
20040604 M.Hurskainen, F.Ruggiero, P.Hägg, T.Pihlajaniemi, and P.Huhtala (2010).
Recombinant human collagen XV regulates cell adhesion and migration.
  J Biol Chem, 285, 5258-5265.  
19693541 M.K.Gordon, and R.A.Hahn (2010).
  Cell Tissue Res, 339, 247-257.  
19469789 F.Meyer, and B.Moussian (2009).
Drosophila multiplexin (Dmp) modulates motor axon pathfinding accuracy.
  Dev Growth Differ, 51, 483-498.  
19304428 L.Zagorchev, and M.J.Mulligan-Kehoe (2009).
Molecular imaging of vessels in mouse models of disease.
  Eur J Radiol, 70, 305-311.  
  19390655 O.Suzuki, E.Kague, K.Bagatini, H.Tu, R.Heljasvaara, L.Carvalhaes, E.Gava, Oliveira, P.Godoi, G.Oliva, G.Kitten, T.Pihlajaniemi, and M.R.Passos-Bueno (2009).
Novel pathogenic mutations and skin biopsy analysis in Knobloch syndrome.
  Mol Vis, 15, 801-809.  
19631658 S.P.Boudko, T.Sasaki, J.Engel, T.F.Lerch, J.Nix, M.S.Chapman, and H.P.Bächinger (2009).
Crystal structure of human collagen XVIII trimerization domain: A novel collagen trimerization Fold.
  J Mol Biol, 392, 787-802.
PDB codes: 3hon 3hsh
18577581 F.Shi, and J.Sottile (2008).
Caveolin-1-dependent beta1 integrin endocytosis is a critical regulator of fibronectin turnover.
  J Cell Sci, 121, 2360-2371.  
18549324 S.Assadian, and J.G.Teodoro (2008).
Regulation of collagen-derived antiangiogenic factors by p53.
  Expert Opin Biol Ther, 8, 941-950.  
17922650 A.A.Terentiev, and N.T.Moldogazieva (2007).
Cell adhesion proteins and alpha-fetoprotein. Similar structural motifs as prerequisites for common functions.
  Biochemistry (Mosc), 72, 920-935.  
17447877 A.V.Digtyar, N.V.Pozdnyakova, N.B.Feldman, S.V.Lutsenko, and S.E.Severin (2007).
Endostatin: current concepts about its biological role and mechanisms of action.
  Biochemistry (Mosc), 72, 235-246.  
17488472 J.M.Rhodes, and M.Simons (2007).
The extracellular matrix and blood vessel formation: not just a scaffold.
  J Cell Mol Med, 11, 176-205.  
17578585 K.Honma, T.Miyata, and T.Ochiya (2007).
Type I collagen gene suppresses tumor growth and invasion of malignant human glioma cells.
  Cancer Cell Int, 7, 12.  
17907150 M.J.Mulligan-Kehoe, M.C.Drinane, J.Mollmark, L.Casciola-Rosen, L.K.Hummers, A.Hall, A.Rosen, F.M.Wigley, and M.Simons (2007).
Antiangiogenic plasma activity in patients with systemic sclerosis.
  Arthritis Rheum, 56, 3448-3458.  
17502049 M.J.Mulligan-Kehoe, and M.Simons (2007).
Current concepts in normal and defective angiogenesis: implications for systemic sclerosis.
  Curr Rheumatol Rep, 9, 173-179.  
17324935 N.Kobayashi, G.Kostka, J.H.Garbe, D.R.Keene, H.P.Bächinger, F.G.Hanisch, D.Markova, T.Tsuda, R.Timpl, M.L.Chu, and T.Sasaki (2007).
A comparative analysis of the fibulin protein family. Biochemical characterization, binding interactions, and tissue localization.
  J Biol Chem, 282, 11805-11816.  
17360545 S.H.George, M.Gertsenstein, K.Vintersten, E.Korets-Smith, J.Murphy, M.E.Stevens, J.J.Haigh, and A.Nagy (2007).
Developmental and adult phenotyping directly from mutant embryonic stem cells.
  Proc Natl Acad Sci U S A, 104, 4455-4460.  
16580972 D.J.Autelitano, A.Rajic, A.I.Smith, M.C.Berndt, L.L.Ilag, and M.Vadas (2006).
The cryptome: a subset of the proteome, comprising cryptic peptides with distinct bioactivities.
  Drug Discov Today, 11, 306-314.  
17082192 J.Khoshnoodi, J.P.Cartailler, K.Alvares, A.Veis, and B.G.Hudson (2006).
Molecular recognition in the assembly of collagens: terminal noncollagenous domains are key recognition modules in the formation of triple helical protomers.
  J Biol Chem, 281, 38117-38121.  
15638918 A.Schmidt, F.Sommer, M.Reiner, T.Klotz, U.Engelmann, K.Addicks, and W.Bloch (2005).
Differential endostatin binding to bladder, prostate and kidney tumour vessels.
  BJU Int, 95, 174-179.  
15751056 F.K.Tan, B.A.Hildebrand, M.S.Lester, D.N.Stivers, S.Pounds, X.Zhou, D.D.Wallis, D.M.Milewicz, J.D.Reveille, M.D.Mayes, L.Jin, and F.C.Arnett (2005).
Classification analysis of the transcriptosome of nonlesional cultured dermal fibroblasts from systemic sclerosis patients with early disease.
  Arthritis Rheum, 52, 865-876.  
15653078 G.Bix, and R.V.Iozzo (2005).
Matrix revolutions: "tails" of basement-membrane components with angiostatic functions.
  Trends Cell Biol, 15, 52-60.  
  15632014 H.Elamaa, R.Sormunen, M.Rehn, R.Soininen, and T.Pihlajaniemi (2005).
Endostatin overexpression specifically in the lens and skin leads to cataract and ultrastructural alterations in basement membranes.
  Am J Pathol, 166, 221-229.  
16138928 J.A.Timmons, E.Jansson, H.Fischer, T.Gustafsson, P.L.Greenhaff, J.Ridden, J.Rachman, and C.J.Sundberg (2005).
Modulation of extracellular matrix genes reflects the magnitude of physiological adaptation to aerobic exercise training in humans.
  BMC Biol, 3, 19.  
15614762 N.Rychkova, S.Stahl, S.Gaetzner, and U.Felbor (2005).
Non-heparan sulfate-binding interactions of endostatin/collagen XVIII in murine development.
  Dev Dyn, 232, 399-407.  
16167328 P.C.Trackman (2005).
Diverse biological functions of extracellular collagen processing enzymes.
  J Cell Biochem, 96, 927-937.  
16234817 R.D.Brammer, S.R.Bramhall, and M.C.Eggo (2005).
Endostatin expression in a pancreatic cell line is modulated by a TNFalpha-dependent elastase.
  Br J Cancer, 93, 1024-1028.  
16064139 R.V.Iozzo (2005).
Basement membrane proteoglycans: from cellar to ceiling.
  Nat Rev Mol Cell Biol, 6, 646-656.  
16115201 S.Stahl, S.Gaetzner, T.D.Mueller, and U.Felbor (2005).
Endostatin phenylalanines 31 and 34 define a receptor binding site.
  Genes Cells, 10, 929-939.  
15188432 A.Schmidt, D.Wenzel, I.Ferring, S.Kazemi, T.Sasaki, J.Hescheler, R.Timpl, K.Addicks, B.K.Fleischmann, and W.Bloch (2004).
Influence of endostatin on embryonic vasculo- and angiogenesis.
  Dev Dyn, 230, 468-480.  
15036261 G.Bellon, L.Martiny, and A.Robinet (2004).
Matrix metalloproteinases and matrikines in angiogenesis.
  Crit Rev Oncol Hematol, 49, 203-220.  
14984764 J.Sottile (2004).
Regulation of angiogenesis by extracellular matrix.
  Biochim Biophys Acta, 1654, 13-22.  
15563309 M.Sund, L.Xie, and R.Kalluri (2004).
The contribution of vascular basement membranes and extracellular matrix to the mechanics of tumor angiogenesis.
  APMIS, 112, 450-462.  
14583633 N.Floquet, S.Pasco, L.Ramont, P.Derreumaux, J.Y.Laronze, J.M.Nuzillard, F.X.Maquart, A.J.Alix, and J.C.Monboisse (2004).
The antitumor properties of the alpha3(IV)-(185-203) peptide from the NC1 domain of type IV collagen (tumstatin) are conformation-dependent.
  J Biol Chem, 279, 2091-2100.  
14695535 O.Menzel, R.C.Bekkeheien, A.Reymond, N.Fukai, E.Boye, G.Kosztolanyi, S.Aftimos, S.Deutsch, H.S.Scott, B.R.Olsen, S.E.Antonarakis, and M.Guipponi (2004).
Knobloch syndrome: novel mutations in COL18A1, evidence for genetic heterogeneity, and a functionally impaired polymorphism in endostatin.
  Hum Mutat, 23, 77-84.  
15036262 S.Pasco, L.Ramont, F.X.Maquart, and J.C.Monboisse (2004).
Control of melanoma progression by various matrikines from basement membrane macromolecules.
  Crit Rev Oncol Hematol, 49, 221-233.  
12920133 A.McAlinden, T.A.Smith, L.J.Sandell, D.Ficheux, D.A.Parry, and D.J.Hulmes (2003).
Alpha-helical coiled-coil oligomerization domains are almost ubiquitous in the collagen superfamily.
  J Biol Chem, 278, 42200-42207.  
12915567 M.F.Kramer, W.J.Cook, F.P.Roth, J.Zhu, H.Holman, D.M.Knipe, and D.M.Coen (2003).
Latent herpes simplex virus infection of sensory neurons alters neuronal gene expression.
  J Virol, 77, 9533-9541.  
12604605 M.Mongiat, J.Fu, R.Oldershaw, R.Greenhalgh, A.M.Gown, and R.V.Iozzo (2003).
Perlecan protein core interacts with extracellular matrix protein 1 (ECM1), a glycoprotein involved in bone formation and angiogenesis.
  J Biol Chem, 278, 17491-17499.  
12435733 M.Mongiat, S.M.Sweeney, J.D.San Antonio, J.Fu, and R.V.Iozzo (2003).
Endorepellin, a novel inhibitor of angiogenesis derived from the C terminus of perlecan.
  J Biol Chem, 278, 4238-4249.  
12710130 N.G.Nikitakis, H.Rivera, M.A.Lopes, H.Siavash, M.A.Reynolds, R.A.Ord, and J.J.Sauk (2003).
Immunohistochemical expression of angiogenesis-related markers in oral squamous cell carcinomas with multiple metastatic lymph nodes.
  Am J Clin Pathol, 119, 574-586.  
12579531 P.S.Amenta, S.Hadad, M.T.Lee, N.Barnard, D.Li, and J.C.Myers (2003).
Loss of types XV and XIX collagen precedes basement membrane invasion in ductal carcinoma of the female breast.
  J Pathol, 199, 298-308.  
12778132 R.Kalluri (2003).
Basement membranes: structure, assembly and role in tumour angiogenesis.
  Nat Rev Cancer, 3, 422-433.  
12778127 R.Timpl, T.Sasaki, G.Kostka, and M.L.Chu (2003).
Fibulins: a versatile family of extracellular matrix proteins.
  Nat Rev Mol Cell Biol, 4, 479-489.  
12837607 S.Schenk, and V.Quaranta (2003).
Tales from the crypt[ic] sites of the extracellular matrix.
  Trends Cell Biol, 13, 366-375.  
11970952 M.Sundaramoorthy, M.Meiyappan, P.Todd, and B.G.Hudson (2002).
Crystal structure of NC1 domains. Structural basis for type IV collagen assembly in basement membranes.
  J Biol Chem, 277, 31142-31153.
PDB code: 1m3d
12376553 N.Ortega, and Z.Werb (2002).
New functional roles for non-collagenous domains of basement membrane collagens.
  J Cell Sci, 115, 4201-4214.  
11995806 S.Saika, Y.Ohnishi, A.Ooshima, C.Y.Liu, and W.W.Kao (2002).
Epithelial repair: roles of extracellular matrix.
  Cornea, 21, S23-S29.  
11937714 Y.Tomono, I.Naito, K.Ando, T.Yonezawa, Y.Sado, S.Hirakawa, J.Arata, T.Okigaki, and Y.Ninomiya (2002).
Epitope-defined monoclonal antibodies against multiplexin collagens demonstrate that type XV and XVIII collagens are expressed in specialized basement membranes.
  Cell Struct Funct, 27, 9.  
11257122 B.D.Ackley, J.R.Crew, H.Elamaa, T.Pihlajaniemi, C.J.Kuo, and J.M.Kramer (2001).
The NC1/endostatin domain of Caenorhabditis elegans type XVIII collagen affects cell migration and axon guidance.
  J Cell Biol, 152, 1219-1232.  
11257123 C.J.Kuo, K.R.LaMontagne, G.Garcia-Cardeña, B.D.Ackley, D.Kalman, S.Park, R.Christofferson, J.Kamihara, Y.H.Ding, K.M.Lo, S.Gillies, J.Folkman, R.C.Mulligan, and K.Javaherian (2001).
Oligomerization-dependent regulation of motility and morphogenesis by the collagen XVIII NC1/endostatin domain.
  J Cell Biol, 152, 1233-1246.  
  11310942 J.Myllyharju, and K.I.Kivirikko (2001).
Collagens and collagen-related diseases.
  Ann Med, 33, 7.  
11158616 L.Eklund, J.Piuhola, J.Komulainen, R.Sormunen, C.Ongvarrasopone, R.Fássler, A.Muona, M.Ilves, H.Ruskoaho, T.E.Takala, and T.Pihlajaniemi (2001).
Lack of type XV collagen causes a skeletal myopathy and cardiovascular defects in mice.
  Proc Natl Acad Sci U S A, 98, 1194-1199.  
  11489925 R.V.Iozzo, and J.D.San Antonio (2001).
Heparan sulfate proteoglycans: heavy hitters in the angiogenesis arena.
  J Clin Invest, 108, 349-355.  
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB code is shown on the right.