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New page: left|200px<br /> <applet load="1ksq" size="450" color="white" frame="true" align="right" spinBox="true" caption="1ksq" /> '''NMR Study of the Third TB Domain from Laten...
 
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[[Image:1ksq.gif|left|200px]]<br />
<applet load="1ksq" size="450" color="white" frame="true" align="right" spinBox="true"
caption="1ksq" />
'''NMR Study of the Third TB Domain from Latent Transforming Growth Factor-beta Binding Protein-1'''<br />


==Overview==
==NMR Study of the Third TB Domain from Latent Transforming Growth Factor-beta Binding Protein-1==
Almost all TGF-beta is secreted as part of a large latent complex. This, complex is formed from three molecules, a latent transforming growth, factor-beta binding protein (LTBP), which plays roles in targeting and, activation, a latency associated peptide (LAP), which regulates latency, and the TGF-beta cytokine. LAP is the TGF-beta pro-peptide that is cleaved, intracellularly prior to secretion, and TGF-beta binds non-covalently to, LAP. Formation of the large latent complex is important for the efficient, secretion of TGF-beta. Previous studies have revealed that the LTBP-LAP, interaction is mediated by intracellular exchange of a single disulphide, bond within the third, and only the third, TB domain (TB3) with LAP. We, have previously reported the structure of a homologous TB domain from, fibrillin-1. However, TB3 contains a two amino acid insertion, not found, in fibrillin-1 TB domains, which is not amenable to molecular modelling., In order to clarify the basis of TB domain function, we have determined, the solution NMR structure of TB3(LTBP1). Comparison with the fibrillin-1, TB domain reveals that the two-residue insertion is associated with a, significant increase in solvent accessibility of one of the disulphide, bonds (linking the second and sixth cysteine residues). Site-directed, mutagenesis and NMR studies indicate that this is the only disulphide bond, that can be removed without perturbing the TB domain fold. Furthermore, a, ring of negatively charged residues has been identified that surrounds, this disulphide bond. Homology modelling suggests that the surface, properties of TB3 domains from different LTBP isoforms correlate with, binding activities. This research provides testable hypotheses regarding, the molecular basis of complex formation between LTBPs and LAPs.
<StructureSection load='1ksq' size='340' side='right'caption='[[1ksq]]' scene=''>
 
== Structural highlights ==
==About this Structure==
<table><tr><td colspan='2'>[[1ksq]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1KSQ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1KSQ FirstGlance]. <br>
1KSQ is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=1KSQ OCA].  
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Solution NMR</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=1ksq FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1ksq OCA], [https://pdbe.org/1ksq PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1ksq RCSB], [https://www.ebi.ac.uk/pdbsum/1ksq PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1ksq ProSAT]</span></td></tr>
==Reference==
</table>
Solution structure of the third TB domain from LTBP1 provides insight into assembly of the large latent complex that sequesters latent TGF-beta., Lack J, O'Leary JM, Knott V, Yuan X, Rifkin DB, Handford PA, Downing AK, J Mol Biol. 2003 Nov 21;334(2):281-91. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=14607119 14607119]
== Disease ==
[https://www.uniprot.org/uniprot/LTBP1_HUMAN LTBP1_HUMAN] Autosomal recessive cutis laxa type 1. The disease is caused by variants affecting the gene represented in this entry.
== Function ==
[https://www.uniprot.org/uniprot/LTBP1_HUMAN LTBP1_HUMAN] Key regulator of transforming growth factor beta (TGFB1, TGFB2 and TGFB3) that controls TGF-beta activation by maintaining it in a latent state during storage in extracellular space (PubMed:2022183, PubMed:8617200, PubMed:8939931). Associates specifically via disulfide bonds with the Latency-associated peptide (LAP), which is the regulatory chain of TGF-beta, and regulates integrin-dependent activation of TGF-beta (PubMed:8617200, PubMed:8939931, PubMed:15184403). Outcompeted by LRRC32/GARP for binding to LAP regulatory chain of TGF-beta (PubMed:22278742).<ref>PMID:15184403</ref> <ref>PMID:2022183</ref> <ref>PMID:22278742</ref> <ref>PMID:8617200</ref> <ref>PMID:8939931</ref>
== 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/ks/1ksq_consurf.spt"</scriptWhenChecked>
    <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.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=1ksq ConSurf].
<div style="clear:both"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
[[Category: Single protein]]
[[Category: Large Structures]]
[[Category: Downing, A.K.]]
[[Category: Downing AK]]
[[Category: Handford, P.A.]]
[[Category: Handford PA]]
[[Category: Knott, V.]]
[[Category: Knott V]]
[[Category: Lack, J.]]
[[Category: Lack J]]
[[Category: Rifkin, D.B.]]
[[Category: O'leary JM]]
[[Category: Yuan, X.]]
[[Category: Rifkin DB]]
[[Category: leary, J.M.O.]]
[[Category: Yuan X]]
[[Category: lap]]
[[Category: latency associated propeptide]]
[[Category: latent transforming growth factor-beta binding protein-1]]
[[Category: ltbp-1]]
[[Category: nmr structure]]
[[Category: tb domain]]
[[Category: tgf-beta]]
 
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Retrieved from "https://proteopedia.org/1ksq"