1tsh: Difference between revisions
New page: left|200px<br /> <applet load="1tsh" size="450" color="white" frame="true" align="right" spinBox="true" caption="1tsh, resolution 1.70Å" /> '''TERTIARY STRUCTURES... |
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[[Image:1tsh.gif|left|200px]]<br /> | [[Image:1tsh.gif|left|200px]]<br /><applet load="1tsh" size="350" color="white" frame="true" align="right" spinBox="true" | ||
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caption="1tsh, resolution 1.70Å" /> | caption="1tsh, resolution 1.70Å" /> | ||
'''TERTIARY STRUCTURES OF THREE AMYLOIDOGENIC TRANSTHYRETIN VARIANTS AND IMPLICATIONS FOR AMYLOID FIBRIL FORMATION'''<br /> | '''TERTIARY STRUCTURES OF THREE AMYLOIDOGENIC TRANSTHYRETIN VARIANTS AND IMPLICATIONS FOR AMYLOID FIBRIL FORMATION'''<br /> | ||
==Overview== | ==Overview== | ||
The most common form of hereditary systemic amyloidosis is familial | The most common form of hereditary systemic amyloidosis is familial amyloidotic polyneuropathy associated with single amino acid changes in the plasma protein transthyretin. So far, high resolution structures of only three amyloidogenic variants (Met30, Ser84, Ile122) and one non-amyloidogenic variant (Thr109) have been reported complemented by X-ray fiber diffraction studies and image reconstruction from electron micrographs of amyloid fibrils. To investigate the role of structural factors in this disease, we extended our studies to other transthyretin variants. We report crystallization and structural investigations of three amyloidogenic (Arg10, Ala60, Tyr77) and two non-amyloidogenic variants (Ser6, Met119). The similarity of these structures to normal transthyretin does not give direct clues to the fibril forming process. Since transthyretin amyloid fibrils contain a major fragment starting at position 49, besides the intact molecule, we calculated the solvent accessibility of residue 48. Indeed, all amyloidogenic variants show an increased main chain solvent exposure when compared to normal transthyretin and non-amyloidogenic variants, which can be postulated to result in increased susceptibility to proteolysis. After limited proteolysis, dimers are incapable of reassociation to native tetramers. We present a model for amyloid fibril formation based on formation of fibrils from N-terminal truncated dimers as building blocks. | ||
==Disease== | ==Disease== | ||
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==About this Structure== | ==About this Structure== | ||
1TSH 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:// | 1TSH 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://oca.weizmann.ac.il/oca-bin/ocashort?id=1TSH OCA]. | ||
==Reference== | ==Reference== | ||
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[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: Single protein]] | [[Category: Single protein]] | ||
[[Category: Benson, M | [[Category: Benson, M D.]] | ||
[[Category: Murrell, J | [[Category: Murrell, J R.]] | ||
[[Category: Schormann, N.]] | [[Category: Schormann, N.]] | ||
[[Category: cerebrospinal fluid]] | [[Category: cerebrospinal fluid]] | ||
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[[Category: transport]] | [[Category: transport]] | ||
''Page seeded by [http:// | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 15:16:48 2008'' | ||
Revision as of 16:16, 21 February 2008
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TERTIARY STRUCTURES OF THREE AMYLOIDOGENIC TRANSTHYRETIN VARIANTS AND IMPLICATIONS FOR AMYLOID FIBRIL FORMATION
OverviewOverview
The most common form of hereditary systemic amyloidosis is familial amyloidotic polyneuropathy associated with single amino acid changes in the plasma protein transthyretin. So far, high resolution structures of only three amyloidogenic variants (Met30, Ser84, Ile122) and one non-amyloidogenic variant (Thr109) have been reported complemented by X-ray fiber diffraction studies and image reconstruction from electron micrographs of amyloid fibrils. To investigate the role of structural factors in this disease, we extended our studies to other transthyretin variants. We report crystallization and structural investigations of three amyloidogenic (Arg10, Ala60, Tyr77) and two non-amyloidogenic variants (Ser6, Met119). The similarity of these structures to normal transthyretin does not give direct clues to the fibril forming process. Since transthyretin amyloid fibrils contain a major fragment starting at position 49, besides the intact molecule, we calculated the solvent accessibility of residue 48. Indeed, all amyloidogenic variants show an increased main chain solvent exposure when compared to normal transthyretin and non-amyloidogenic variants, which can be postulated to result in increased susceptibility to proteolysis. After limited proteolysis, dimers are incapable of reassociation to native tetramers. We present a model for amyloid fibril formation based on formation of fibrils from N-terminal truncated dimers as building blocks.
DiseaseDisease
Known diseases associated with this structure: Amyloid neuropathy, familial, several allelic types OMIM:[176300], Amyloidosis, senile systemic OMIM:[176300], Carpal tunnel syndrome, familial OMIM:[176300], Dystransthyretinemic hyperthyroxinemia OMIM:[176300]
About this StructureAbout this Structure
1TSH is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.
ReferenceReference
Tertiary structures of amyloidogenic and non-amyloidogenic transthyretin variants: new model for amyloid fibril formation., Schormann N, Murrell JR, Benson MD, Amyloid. 1998 Sep;5(3):175-87. PMID:9818054
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