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| - | [[Image:1gko.gif|left|200px]] | + | {{Seed}} |
| | + | [[Image:1gko.png|left|200px]] |
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| | {{STRUCTURE_1gko| PDB=1gko | SCENE= }} | | {{STRUCTURE_1gko| PDB=1gko | SCENE= }} |
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| - | '''AN ENGINEERED TRANSTHYRETIN MONOMER THAT IS NON-AMYLOIDOGENIC-UNLESS PARTIALLY DENATURED'''
| + | ===AN ENGINEERED TRANSTHYRETIN MONOMER THAT IS NON-AMYLOIDOGENIC-UNLESS PARTIALLY DENATURED=== |
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| - | ==Overview==
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| - | Transthyretin (TTR) is a soluble human plasma protein that can be converted into amyloid by acid-mediated dissociation of the homotetramer into monomers. The pH required for disassembly also results in tertiary structural changes within the monomeric subunits. To understand whether these tertiary structural changes are required for amyloidogenicity, we created the Phe87Met/Leu110Met TTR variant (M-TTR) that is monomeric according to analytical ultracentrifugation and gel filtration analyses and nonamyloidogenic at neutral pH. Results from far- and near-UV circular dichroism spectroscopy, one-dimensional proton NMR spectroscopy, and X-ray crystallography, as well as the ability of M-TTR to form a complex with retinol binding protein, indicate that M-TTR forms a tertiary structure at pH 7 that is very similar if not identical to that found within the tetramer. Reducing the pH results in tertiary structural changes within the M-TTR monomer, rendering it amyloidogenic, demonstrating the requirement for partial denaturation. M-TTR exhibits stability toward acid and urea denaturation that is nearly identical to that characterizing wild-type (WT) TTR at low concentrations (0.01-0.1 mg/mL), where monomeric WT TTR is significantly populated at intermediate urea concentrations prior to the tertiary structural transition. However, the kinetics of denaturation and fibril formation are much faster for M-TTR than for tetrameric WT TTR, particularly at near-physiological concentrations, because of the barrier associated with the tetramer to folded monomer preequilibrium. These results demonstrate that the tetramer to folded monomer transition is insufficient for fibril formation; further tertiary structural changes within the monomer are required.
| + | The line below this paragraph, {{ABSTRACT_PUBMED_11560492}}, adds the Publication Abstract to the page |
| | + | (as it appears on PubMed at http://www.pubmed.gov), where 11560492 is the PubMed ID number. |
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| | + | {{ABSTRACT_PUBMED_11560492}} |
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| | ==About this Structure== | | ==About this Structure== |
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| | [[Category: Transthyretin]] | | [[Category: Transthyretin]] |
| | [[Category: Ttr]] | | [[Category: Ttr]] |
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Fri May 2 17:41:53 2008'' | + | |
| | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Tue Jul 1 05:26:57 2008'' |
Revision as of 02:26, 1 July 2008
Template:STRUCTURE 1gko
AN ENGINEERED TRANSTHYRETIN MONOMER THAT IS NON-AMYLOIDOGENIC-UNLESS PARTIALLY DENATURED
Template:ABSTRACT PUBMED 11560492
About this Structure
1GKO is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.
Reference
An engineered transthyretin monomer that is nonamyloidogenic, unless it is partially denatured., Jiang X, Smith CS, Petrassi HM, Hammarstrom P, White JT, Sacchettini JC, Kelly JW, Biochemistry. 2001 Sep 25;40(38):11442-52. PMID:11560492
Page seeded by OCA on Tue Jul 1 05:26:57 2008
