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| - | {{Seed}} | |
| - | [[Image:3kfd.jpg|left|200px]] | |
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| - | <!--
| + | ==Ternary complex of TGF-b1 reveals isoform-specific ligand recognition and receptor recruitment in the superfamily== |
| - | The line below this paragraph, containing "STRUCTURE_3kfd", creates the "Structure Box" on the page.
| + | <StructureSection load='3kfd' size='340' side='right'caption='[[3kfd]], [[Resolution|resolution]] 3.00Å' scene=''> |
| - | You may change the PDB parameter (which sets the PDB file loaded into the applet) | + | == Structural highlights == |
| - | or the SCENE parameter (which sets the initial scene displayed when the page is loaded),
| + | <table><tr><td colspan='2'>[[3kfd]] is a 12 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3KFD OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3KFD FirstGlance]. <br> |
| - | or leave the SCENE parameter empty for the default display.
| + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.995Å</td></tr> |
| - | --> | + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=3kfd FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3kfd OCA], [https://pdbe.org/3kfd PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3kfd RCSB], [https://www.ebi.ac.uk/pdbsum/3kfd PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3kfd ProSAT]</span></td></tr> |
| - | {{STRUCTURE_3kfd| PDB=3kfd | SCENE= }}
| + | </table> |
| | + | == Disease == |
| | + | [https://www.uniprot.org/uniprot/TGFB1_HUMAN TGFB1_HUMAN] Defects in TGFB1 are the cause of Camurati-Engelmann disease (CE) [MIM:[https://omim.org/entry/131300 131300]; also known as progressive diaphyseal dysplasia 1 (DPD1). CE is an autosomal dominant disorder characterized by hyperostosis and sclerosis of the diaphyses of long bones. The disease typically presents in early childhood with pain, muscular weakness and waddling gait, and in some cases other features such as exophthalmos, facial paralysis, hearing difficulties and loss of vision.<ref>PMID:10973241</ref> <ref>PMID:11062463</ref> <ref>PMID:12493741</ref> <ref>PMID:12843182</ref> <ref>PMID:15103729</ref> |
| | + | == Function == |
| | + | [https://www.uniprot.org/uniprot/TGFB1_HUMAN TGFB1_HUMAN] Multifunctional protein that controls proliferation, differentiation and other functions in many cell types. Many cells synthesize TGFB1 and have specific receptors for it. It positively and negatively regulates many other growth factors. It plays an important role in bone remodeling as it is a potent stimulator of osteoblastic bone formation, causing chemotaxis, proliferation and differentiation in committed osteoblasts. |
| | + | == Evolutionary Conservation == |
| | + | [[Image:Consurf_key_small.gif|200px|right]] |
| | + | Check<jmol> |
| | + | <jmolCheckbox> |
| | + | <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/kf/3kfd_consurf.spt"</scriptWhenChecked> |
| | + | <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview03.spt</scriptWhenUnchecked> |
| | + | <text>to colour the structure by Evolutionary Conservation</text> |
| | + | </jmolCheckbox> |
| | + | </jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=3kfd ConSurf]. |
| | + | <div style="clear:both"></div> |
| | + | <div style="background-color:#fffaf0;"> |
| | + | == Publication Abstract from PubMed == |
| | + | Transforming growth factor (TGF)-beta1, -beta2, and -beta3 are 25-kDa homodimeric polypeptides that play crucial nonoverlapping roles in embryogenesis, tissue development, carcinogenesis, and immune regulation. Here we report the 3.0-A resolution crystal structure of the ternary complex between human TGF-beta1 and the extracellular domains of its type I and type II receptors, TbetaRI and TbetaRII. The TGF-beta1 ternary complex structure is similar to previously reported TGF-beta3 complex except with a 10 degrees rotation in TbetaRI docking orientation. Quantitative binding studies showed distinct kinetics between the receptors and the isoforms of TGF-beta. TbetaRI showed significant binding to TGF-beta2 and TGF-beta3 but not TGF-beta1, and the binding to all three isoforms of TGF-beta was enhanced considerably in the presence of TbetaRII. The preference of TGF-beta2 to TbetaRI suggests a variation in its receptor recruitment in vivo. Although TGF-beta1 and TGF-beta3 bind and assemble their ternary complexes in a similar manner, their structural differences together with differences in the affinities and kinetics of their receptor binding may underlie their unique biological activities. Structural comparisons revealed that the receptor-ligand pairing in the TGF-beta superfamily is dictated by unique insertions, deletions, and disulfide bonds rather than amino acid conservation at the interface. The binding mode of TbetaRII on TGF-beta is unique to TGF-betas, whereas that of type II receptor for bone morphogenetic protein on bone morphogenetic protein appears common to all other cytokines in the superfamily. Further, extensive hydrogen bonds and salt bridges are present at the high affinity cytokine-receptor interfaces, whereas hydrophobic interactions dominate the low affinity receptor-ligand interfaces. |
| | | | |
| - | ===Ternary complex of TGF-b1 reveals isoform-specific ligand recognition and receptor recruitment in the superfamily===
| + | Ternary complex of transforming growth factor-beta1 reveals isoform-specific ligand recognition and receptor recruitment in the superfamily.,Radaev S, Zou Z, Huang T, Lafer EM, Hinck AP, Sun PD J Biol Chem. 2010 May 7;285(19):14806-14. Epub 2010 Mar 5. PMID:20207738<ref>PMID:20207738</ref> |
| | | | |
| | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> |
| | + | </div> |
| | + | <div class="pdbe-citations 3kfd" style="background-color:#fffaf0;"></div> |
| | | | |
| - | ==Disease== | + | ==See Also== |
| - | Known disease associated with this structure: Colorectal cancer, hereditary nonpolyposis, type 6 OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=190182 190182]], Esophageal cancer OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=190182 190182]], Loeys-Dietz syndrome, type 1B OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=190182 190182]], Loeys-Dietz syndrome, type 2B OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=190182 190182]], Loeys-Dietz syndrome, type 1A OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=190181 190181]], Loeys-Dietz syndrome, type 2A OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=190181 190181]]
| + | *[[TGF-beta receptor 3D structures|TGF-beta receptor 3D structures]] |
| - | | + | == References == |
| - | ==About this Structure== | + | <references/> |
| - | 3KFD is a 12 chains structure with sequences from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3KFD OCA].
| + | __TOC__ |
| | + | </StructureSection> |
| | [[Category: Homo sapiens]] | | [[Category: Homo sapiens]] |
| - | [[Category: Radaev, S.]] | + | [[Category: Large Structures]] |
| - | [[Category: Sun, P D.]] | + | [[Category: Radaev S]] |
| - | [[Category: Cytokine-cytokine receptor complex]] | + | [[Category: Sun PD]] |
| - | [[Category: Growth factor]]
| + | |
| - | [[Category: Receptor]]
| + | |
| - | [[Category: Serine/threonine-protein kinase]]
| + | |
| - | [[Category: Tbri]]
| + | |
| - | [[Category: Tbrii]]
| + | |
| - | [[Category: Tgf-b1]]
| + | |
| - | [[Category: Tgf-beta]]
| + | |
| - | [[Category: Tgf-beta receptor type-1]]
| + | |
| - | [[Category: Tgf-beta receptor type-2]]
| + | |
| - | | + | |
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Wed Mar 3 17:15:11 2010''
| + | |
| Structural highlights
Disease
TGFB1_HUMAN Defects in TGFB1 are the cause of Camurati-Engelmann disease (CE) [MIM:131300; also known as progressive diaphyseal dysplasia 1 (DPD1). CE is an autosomal dominant disorder characterized by hyperostosis and sclerosis of the diaphyses of long bones. The disease typically presents in early childhood with pain, muscular weakness and waddling gait, and in some cases other features such as exophthalmos, facial paralysis, hearing difficulties and loss of vision.[1] [2] [3] [4] [5]
Function
TGFB1_HUMAN Multifunctional protein that controls proliferation, differentiation and other functions in many cell types. Many cells synthesize TGFB1 and have specific receptors for it. It positively and negatively regulates many other growth factors. It plays an important role in bone remodeling as it is a potent stimulator of osteoblastic bone formation, causing chemotaxis, proliferation and differentiation in committed osteoblasts.
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
Transforming growth factor (TGF)-beta1, -beta2, and -beta3 are 25-kDa homodimeric polypeptides that play crucial nonoverlapping roles in embryogenesis, tissue development, carcinogenesis, and immune regulation. Here we report the 3.0-A resolution crystal structure of the ternary complex between human TGF-beta1 and the extracellular domains of its type I and type II receptors, TbetaRI and TbetaRII. The TGF-beta1 ternary complex structure is similar to previously reported TGF-beta3 complex except with a 10 degrees rotation in TbetaRI docking orientation. Quantitative binding studies showed distinct kinetics between the receptors and the isoforms of TGF-beta. TbetaRI showed significant binding to TGF-beta2 and TGF-beta3 but not TGF-beta1, and the binding to all three isoforms of TGF-beta was enhanced considerably in the presence of TbetaRII. The preference of TGF-beta2 to TbetaRI suggests a variation in its receptor recruitment in vivo. Although TGF-beta1 and TGF-beta3 bind and assemble their ternary complexes in a similar manner, their structural differences together with differences in the affinities and kinetics of their receptor binding may underlie their unique biological activities. Structural comparisons revealed that the receptor-ligand pairing in the TGF-beta superfamily is dictated by unique insertions, deletions, and disulfide bonds rather than amino acid conservation at the interface. The binding mode of TbetaRII on TGF-beta is unique to TGF-betas, whereas that of type II receptor for bone morphogenetic protein on bone morphogenetic protein appears common to all other cytokines in the superfamily. Further, extensive hydrogen bonds and salt bridges are present at the high affinity cytokine-receptor interfaces, whereas hydrophobic interactions dominate the low affinity receptor-ligand interfaces.
Ternary complex of transforming growth factor-beta1 reveals isoform-specific ligand recognition and receptor recruitment in the superfamily.,Radaev S, Zou Z, Huang T, Lafer EM, Hinck AP, Sun PD J Biol Chem. 2010 May 7;285(19):14806-14. Epub 2010 Mar 5. PMID:20207738[6]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Kinoshita A, Saito T, Tomita H, Makita Y, Yoshida K, Ghadami M, Yamada K, Kondo S, Ikegawa S, Nishimura G, Fukushima Y, Nakagomi T, Saito H, Sugimoto T, Kamegaya M, Hisa K, Murray JC, Taniguchi N, Niikawa N, Yoshiura K. Domain-specific mutations in TGFB1 result in Camurati-Engelmann disease. Nat Genet. 2000 Sep;26(1):19-20. PMID:10973241 doi:10.1038/79128
- ↑ Janssens K, Gershoni-Baruch R, Guanabens N, Migone N, Ralston S, Bonduelle M, Lissens W, Van Maldergem L, Vanhoenacker F, Verbruggen L, Van Hul W. Mutations in the gene encoding the latency-associated peptide of TGF-beta 1 cause Camurati-Engelmann disease. Nat Genet. 2000 Nov;26(3):273-5. PMID:11062463 doi:10.1038/81563
- ↑ Janssens K, ten Dijke P, Ralston SH, Bergmann C, Van Hul W. Transforming growth factor-beta 1 mutations in Camurati-Engelmann disease lead to increased signaling by altering either activation or secretion of the mutant protein. J Biol Chem. 2003 Feb 28;278(9):7718-24. Epub 2002 Dec 18. PMID:12493741 doi:10.1074/jbc.M208857200
- ↑ McGowan NW, MacPherson H, Janssens K, Van Hul W, Frith JC, Fraser WD, Ralston SH, Helfrich MH. A mutation affecting the latency-associated peptide of TGFbeta1 in Camurati-Engelmann disease enhances osteoclast formation in vitro. J Clin Endocrinol Metab. 2003 Jul;88(7):3321-6. PMID:12843182
- ↑ Kinoshita A, Fukumaki Y, Shirahama S, Miyahara A, Nishimura G, Haga N, Namba A, Ueda H, Hayashi H, Ikegawa S, Seidel J, Niikawa N, Yoshiura K. TGFB1 mutations in four new families with Camurati-Engelmann disease: confirmation of independently arising LAP-domain-specific mutations. Am J Med Genet A. 2004 May 15;127A(1):104-7. PMID:15103729 doi:10.1002/ajmg.a.20671
- ↑ Radaev S, Zou Z, Huang T, Lafer EM, Hinck AP, Sun PD. Ternary complex of transforming growth factor-beta1 reveals isoform-specific ligand recognition and receptor recruitment in the superfamily. J Biol Chem. 2010 May 7;285(19):14806-14. Epub 2010 Mar 5. PMID:20207738 doi:10.1074/jbc.M109.079921
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