Removal of pattern-breaking sequences in microtubule binding repeats
produces instantaneous tau aggregation and toxicity
A. Iliev, S. Ganesan, G. Bunt, and F. Wouters. J Biol Chem, 281 (48):
37195-204(December 2006)Iliev, Asparouh Iliev Ganesan, Sundar Bunt, Gertrude Wouters, Fred
Silvester Research Support, Non-U.S. Gov't United States The Journal
of biological chemistry J Biol Chem. 2006 Dec 1;281(48):37195-204.
Epub 2006 Sep 27..
Abstract
Aggregated and highly phosphorylated tau protein is a pathological
hallmark of Alzheimer's disease (AD) and other tauopathies. We identified
motifs of alternating polar and apolar amino acids within the microtubule-binding
repeats of tau which were interrupted by small breaking stretches.
Minimal mutation of these breaking sequences yielded a unique instantly
aggregating tau mutant containing longer stretches of polar/apolar
amino acids without losing its microtubule-binding capacity. These
modifications produced rapid aggregation and cytotoxicity with accompanying
occurrence of pathologic tau phosphoepitopes (AT8, AT180, AT270,
AT100, Ser(422), and PHF-1) and conformational epitopes (MC-1 and
Alz50) in cells. Similar to pathological tau in the pretangle state,
toxicity appeared to occur early without the requirement for extensive
fibril formation. Thus, our mutant protein provides a novel platform
for the investigation of the molecular mechanisms for toxicity and
cellular behavior of pathologically aggregated tau proteins and the
identification of its interaction partners.
Iliev, Asparouh Iliev Ganesan, Sundar Bunt, Gertrude Wouters, Fred
Silvester Research Support, Non-U.S. Gov't United States The Journal
of biological chemistry J Biol Chem. 2006 Dec 1;281(48):37195-204.
Epub 2006 Sep 27.
%0 Journal Article
%1 Iliev2006
%A Iliev, A. I.
%A Ganesan, S.
%A Bunt, G.
%A Wouters, F. S.
%D 2006
%J J Biol Chem
%K Acid Amino Animals C57BL CHO Cell Cricetinae Data Epitopes/chemistry Hippocampus/metabolism Homology, Humans Line, Mice Microtubules/*chemistry Molecular Neurons/metabolism Phosphorylation Proteins/*chemistry Sequence Tumor tau
%N 48
%P 37195-204
%T Removal of pattern-breaking sequences in microtubule binding repeats
produces instantaneous tau aggregation and toxicity
%U http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17008320
%V 281
%X Aggregated and highly phosphorylated tau protein is a pathological
hallmark of Alzheimer's disease (AD) and other tauopathies. We identified
motifs of alternating polar and apolar amino acids within the microtubule-binding
repeats of tau which were interrupted by small breaking stretches.
Minimal mutation of these breaking sequences yielded a unique instantly
aggregating tau mutant containing longer stretches of polar/apolar
amino acids without losing its microtubule-binding capacity. These
modifications produced rapid aggregation and cytotoxicity with accompanying
occurrence of pathologic tau phosphoepitopes (AT8, AT180, AT270,
AT100, Ser(422), and PHF-1) and conformational epitopes (MC-1 and
Alz50) in cells. Similar to pathological tau in the pretangle state,
toxicity appeared to occur early without the requirement for extensive
fibril formation. Thus, our mutant protein provides a novel platform
for the investigation of the molecular mechanisms for toxicity and
cellular behavior of pathologically aggregated tau proteins and the
identification of its interaction partners.
@article{Iliev2006,
abstract = {Aggregated and highly phosphorylated tau protein is a pathological
hallmark of Alzheimer's disease (AD) and other tauopathies. We identified
motifs of alternating polar and apolar amino acids within the microtubule-binding
repeats of tau which were interrupted by small breaking stretches.
Minimal mutation of these breaking sequences yielded a unique instantly
aggregating tau mutant containing longer stretches of polar/apolar
amino acids without losing its microtubule-binding capacity. These
modifications produced rapid aggregation and cytotoxicity with accompanying
occurrence of pathologic tau phosphoepitopes (AT8, AT180, AT270,
AT100, Ser(422), and PHF-1) and conformational epitopes (MC-1 and
Alz50) in cells. Similar to pathological tau in the pretangle state,
toxicity appeared to occur early without the requirement for extensive
fibril formation. Thus, our mutant protein provides a novel platform
for the investigation of the molecular mechanisms for toxicity and
cellular behavior of pathologically aggregated tau proteins and the
identification of its interaction partners.},
added-at = {2010-12-14T18:12:02.000+0100},
author = {Iliev, A. I. and Ganesan, S. and Bunt, G. and Wouters, F. S.},
biburl = {https://www.bibsonomy.org/bibtex/2f0bcf8d3ad8c82d25aea0f34689d51e6/pharmawuerz},
endnotereftype = {Journal Article},
interhash = {faf319b10294ef8550690423acdcf66c},
intrahash = {f0bcf8d3ad8c82d25aea0f34689d51e6},
issn = {0021-9258 (Print) 0021-9258 (Linking)},
journal = {J Biol Chem},
keywords = {Acid Amino Animals C57BL CHO Cell Cricetinae Data Epitopes/chemistry Hippocampus/metabolism Homology, Humans Line, Mice Microtubules/*chemistry Molecular Neurons/metabolism Phosphorylation Proteins/*chemistry Sequence Tumor tau},
month = {Dec 1},
note = {Iliev, Asparouh Iliev Ganesan, Sundar Bunt, Gertrude Wouters, Fred
Silvester Research Support, Non-U.S. Gov't United States The Journal
of biological chemistry J Biol Chem. 2006 Dec 1;281(48):37195-204.
Epub 2006 Sep 27.},
number = 48,
pages = {37195-204},
shorttitle = {Removal of pattern-breaking sequences in microtubule binding repeats
produces instantaneous tau aggregation and toxicity},
timestamp = {2010-12-14T18:22:13.000+0100},
title = {Removal of pattern-breaking sequences in microtubule binding repeats
produces instantaneous tau aggregation and toxicity},
url = {http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17008320},
volume = 281,
year = 2006
}