We apologize for Proteopedia being slow to respond. For the past two years, a new implementation of Proteopedia has been being built. Soon, it will replace this 18-year old system. All existing content will be moved to the new system at a date that will be announced here.

1qwh

From Proteopedia

(Difference between revisions)
Jump to: navigation, search
(New page: 200px<br /> <applet load="1qwh" size="450" color="white" frame="true" align="right" spinBox="true" caption="1qwh, resolution 1.36&Aring;" /> '''a covalent dimer of...)
Current revision (10:06, 16 August 2023) (edit) (undo)
 
(17 intermediate revisions not shown.)
Line 1: Line 1:
-
[[Image:1qwh.gif|left|200px]]<br />
 
-
<applet load="1qwh" size="450" color="white" frame="true" align="right" spinBox="true"
 
-
caption="1qwh, resolution 1.36&Aring;" />
 
-
'''a covalent dimer of transthyretin that affects the amyloid pathway'''<br />
 
-
==Overview==
+
==a covalent dimer of transthyretin that affects the amyloid pathway==
-
The amyloidogenic homotetrameric protein transthyretin (TTR) must undergo, rate-limiting dissociation to partially denatured monomers in order to, aggregate. TTR contains two distinct quaternary interfaces, one of which, defines the binding sites for thyroxine and small-molecule amyloidogenesis, inhibitors. Kinetic stabilization of the tetramer can be accomplished, either by the binding of amyloidogenesis inhibitors selectively to the, native state over the dissociative transition state or by the introduction, of trans-suppressor subunits (T119M) into heterotetramers to destabilize, the dissociative transition state. In each case, increasing the, dissociation activation barrier prevents tetramer dissociation. Herein, we, demonstrate that tethering two subunits whose quaternary interface defines, the thyroxine binding site also dramatically increases the barrier for, tetramer dissociation, apparently by destabilization of the dissociative, transition state. The tethered construct (TTR-L-TTR)2 is structurally and, functionally equivalent to wild-type TTR. Urea is unable to denature, (TTR-L-TTR)2, yet it is able to maintain the denatured state once, denaturation is achieved by GdnHCl treatment, suggesting that (TTR-L-TTR)2, is kinetically rather than thermodynamically stabilized, consistent with, the identical wild-type TTR and (TTR-L-TTR)2 GdnHCl denaturation curves., Studies focused on a construct containing a single TTR-L-TTR chain and two, normal monomer subunits establish that alteration of only one quaternary, structural interface is sufficient to impose kinetic stabilization on the, entire quaternary structure.
+
<StructureSection load='1qwh' size='340' side='right'caption='[[1qwh]], [[Resolution|resolution]] 1.36&Aring;' scene=''>
 +
== Structural highlights ==
 +
<table><tr><td colspan='2'>[[1qwh]] is a 2 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=1QWH OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1QWH FirstGlance]. <br>
 +
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.36&#8491;</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=1qwh FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1qwh OCA], [https://pdbe.org/1qwh PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1qwh RCSB], [https://www.ebi.ac.uk/pdbsum/1qwh PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1qwh ProSAT]</span></td></tr>
 +
</table>
 +
== Disease ==
 +
[https://www.uniprot.org/uniprot/TTHY_HUMAN TTHY_HUMAN] Defects in TTR are the cause of amyloidosis transthyretin-related (AMYL-TTR) [MIM:[https://omim.org/entry/105210 105210]. A hereditary generalized amyloidosis due to transthyretin amyloid deposition. Protein fibrils can form in different tissues leading to amyloid polyneuropathies, amyloidotic cardiomyopathy, carpal tunnel syndrome, systemic senile amyloidosis. The disease includes leptomeningeal amyloidosis that is characterized by primary involvement of the central nervous system. Neuropathologic examination shows amyloid in the walls of leptomeningeal vessels, in pia arachnoid, and subpial deposits. Some patients also develop vitreous amyloid deposition that leads to visual impairment (oculoleptomeningeal amyloidosis). Clinical features include seizures, stroke-like episodes, dementia, psychomotor deterioration, variable amyloid deposition in the vitreous humor.<ref>PMID:11243784</ref> <ref>PMID:15735344</ref> <ref>PMID:19167329</ref> <ref>PMID:3818577</ref> <ref>PMID:3022108</ref> <ref>PMID:6651852</ref> <ref>PMID:6583672</ref> <ref>PMID:3135807</ref> <ref>PMID:1517749</ref> <ref>PMID:1932142</ref> <ref>PMID:7923855</ref> <ref>PMID:8382610</ref> <ref>PMID:8428915</ref> <ref>PMID:9733771</ref> <ref>PMID:12403615</ref> <ref>PMID:16185074</ref> <ref>PMID:16627944</ref> <ref>PMID:6487335</ref> <ref>PMID:3722385</ref> <ref>PMID:2891727</ref> <ref>PMID:2161654</ref> <ref>PMID:2363717</ref> <ref>PMID:1656975</ref> <ref>PMID:2046936</ref> <ref>PMID:1570831</ref> <ref>PMID:1734866</ref> <ref>PMID:1520326</ref> <ref>PMID:1520336</ref> <ref>PMID:1544214</ref> <ref>PMID:1351039</ref> <ref>PMID:1301926</ref> <ref>PMID:1362222</ref> <ref>PMID:1436517</ref> <ref>PMID:8352764</ref> <ref>PMID:8038017</ref> <ref>PMID:8257997</ref> <ref>PMID:8095302</ref> <ref>PMID:1997217</ref> <ref>PMID:8019560</ref> <ref>PMID:8081397</ref> <ref>PMID:7914929</ref> <ref>PMID:8133316</ref> <ref>PMID:7910950</ref> <ref>PMID:7655883</ref> <ref>PMID:7850982</ref> <ref>PMID:8579098</ref> <ref>PMID:9066351</ref> <ref>PMID:8990019</ref> <ref>PMID:9605286</ref> <ref>PMID:10036587</ref> <ref>PMID:10627135</ref> <ref>PMID:10694917</ref> <ref>PMID:10211412</ref> <ref>PMID:10439117</ref> <ref>PMID:10611950</ref> <ref>PMID:10071047</ref> <ref>PMID:10436378</ref> <ref>PMID:10842705</ref> <ref>PMID:10842718</ref> <ref>PMID:10882995</ref> <ref>PMID:11445644</ref> <ref>PMID:12557757</ref> <ref>PMID:11866053</ref> <ref>PMID:12050338</ref> <ref>PMID:12771253</ref> <ref>PMID:15214015</ref> <ref>PMID:15478468</ref> <ref>PMID:15217993</ref> <ref>PMID:17453626</ref> <ref>PMID:17577687</ref> <ref>PMID:17503405</ref> <ref>PMID:17635579</ref> Defects in TTR are a cause of hyperthyroxinemia dystransthyretinemic euthyroidal (HTDE) [MIM:[https://omim.org/entry/145680 145680]. It is a condition characterized by elevation of total and free thyroxine in healthy, euthyroid persons without detectable binding protein abnormalities.<ref>PMID:1979335</ref> Defects in TTR are a cause of carpal tunnel syndrome type 1 (CTS1) [MIM:[https://omim.org/entry/115430 115430]. It is a condition characterized by entrapment of the median nerve within the carpal tunnel. Symptoms include burning pain and paresthesias involving the ventral surface of the hand and fingers which may radiate proximally. Impairment of sensation in the distribution of the median nerve and thenar muscle atrophy may occur. This condition may be associated with repetitive occupational trauma, wrist injuries, amyloid neuropathies, rheumatoid arthritis.<ref>PMID:8309582</ref>
 +
== Function ==
 +
[https://www.uniprot.org/uniprot/TTHY_HUMAN TTHY_HUMAN] Thyroid hormone-binding protein. Probably transports thyroxine from the bloodstream to the brain.<ref>PMID:3714052</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/qw/1qwh_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=1qwh ConSurf].
 +
<div style="clear:both"></div>
 +
<div style="background-color:#fffaf0;">
 +
== Publication Abstract from PubMed ==
 +
The amyloidogenic homotetrameric protein transthyretin (TTR) must undergo rate-limiting dissociation to partially denatured monomers in order to aggregate. TTR contains two distinct quaternary interfaces, one of which defines the binding sites for thyroxine and small-molecule amyloidogenesis inhibitors. Kinetic stabilization of the tetramer can be accomplished either by the binding of amyloidogenesis inhibitors selectively to the native state over the dissociative transition state or by the introduction of trans-suppressor subunits (T119M) into heterotetramers to destabilize the dissociative transition state. In each case, increasing the dissociation activation barrier prevents tetramer dissociation. Herein, we demonstrate that tethering two subunits whose quaternary interface defines the thyroxine binding site also dramatically increases the barrier for tetramer dissociation, apparently by destabilization of the dissociative transition state. The tethered construct (TTR-L-TTR)2 is structurally and functionally equivalent to wild-type TTR. Urea is unable to denature (TTR-L-TTR)2, yet it is able to maintain the denatured state once denaturation is achieved by GdnHCl treatment, suggesting that (TTR-L-TTR)2 is kinetically rather than thermodynamically stabilized, consistent with the identical wild-type TTR and (TTR-L-TTR)2 GdnHCl denaturation curves. Studies focused on a construct containing a single TTR-L-TTR chain and two normal monomer subunits establish that alteration of only one quaternary structural interface is sufficient to impose kinetic stabilization on the entire quaternary structure.
-
==Disease==
+
Kinetic stabilization of the native state by protein engineering: implications for inhibition of transthyretin amyloidogenesis.,Foss TR, Kelker MS, Wiseman RL, Wilson IA, Kelly JW J Mol Biol. 2005 Apr 8;347(4):841-54. PMID:15769474<ref>PMID:15769474</ref>
-
Known diseases associated with this structure: Amyloid neuropathy, familial, several allelic types OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=176300 176300]], Amyloidosis, senile systemic OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=176300 176300]], Carpal tunnel syndrome, familial OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=176300 176300]], Dystransthyretinemic hyperthyroxinemia OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=176300 176300]]
+
-
==About this Structure==
+
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-
1QWH 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=1QWH OCA].
+
</div>
 +
<div class="pdbe-citations 1qwh" style="background-color:#fffaf0;"></div>
-
==Reference==
+
==See Also==
-
Kinetic stabilization of the native state by protein engineering: implications for inhibition of transthyretin amyloidogenesis., Foss TR, Kelker MS, Wiseman RL, Wilson IA, Kelly JW, J Mol Biol. 2005 Apr 8;347(4):841-54. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=15769474 15769474]
+
*[[Transthyretin 3D structures|Transthyretin 3D structures]]
 +
== References ==
 +
<references/>
 +
__TOC__
 +
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
-
[[Category: Single protein]]
+
[[Category: Large Structures]]
-
[[Category: Foss, T.]]
+
[[Category: Foss T]]
-
[[Category: Kelker, M.S.]]
+
[[Category: Kelker MS]]
-
[[Category: Wilson, I.A.]]
+
[[Category: Wilson IA]]
-
[[Category: binding protein]]
+
-
[[Category: cerebrospinal fluid]]
+
-
[[Category: disease mutation]]
+
-
[[Category: liver]]
+
-
[[Category: plasma]]
+
-
[[Category: polymorphism]]
+
-
[[Category: polyneuropathy]]
+
-
[[Category: signal]]
+
-
[[Category: thyroid hormone]]
+
-
[[Category: thyroxine]]
+
-
[[Category: transport]]
+
-
 
+
-
''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov 12 18:57:05 2007''
+

Current revision

a covalent dimer of transthyretin that affects the amyloid pathway

PDB ID 1qwh

Drag the structure with the mouse to rotate

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/1qwh"
Personal tools