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1qwh

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[[Image:1qwh.gif|left|200px]]
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{{STRUCTURE_1qwh| PDB=1qwh | SCENE= }}
{{STRUCTURE_1qwh| PDB=1qwh | SCENE= }}
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'''a covalent dimer of transthyretin that affects the amyloid pathway'''
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===a covalent dimer of transthyretin that affects the amyloid pathway===
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==Overview==
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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.
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(as it appears on PubMed at http://www.pubmed.gov), where 15769474 is the PubMed ID number.
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{{ABSTRACT_PUBMED_15769474}}
==About this Structure==
==About this Structure==
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[[Category: Thyroxine]]
[[Category: Thyroxine]]
[[Category: Transport]]
[[Category: Transport]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sat May 3 06:46:53 2008''
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun Jul 27 15:08:24 2008''

Revision as of 12:08, 27 July 2008

Image:1qwh.png

Template:STRUCTURE 1qwh

a covalent dimer of transthyretin that affects the amyloid pathway

Template:ABSTRACT PUBMED 15769474

About this Structure

1QWH is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.

Reference

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

Page seeded by OCA on Sun Jul 27 15:08:24 2008

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