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J. Biol. Chem., Vol. 275, Issue 49, 38182-38189, December 8, 2000
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From the Neuroscience Research Institute and Department of
Molecular, Cellular, and Developmental Biology, University of
California, Santa Barbara, California 93106
Tau, MAP2, and MAP4 are members of a
microtubule-associated protein (MAP) family that are each expressed as
"3-repeat" and "4-repeat" isoforms. These isoforms arise from
tightly controlled tissue-specific and/or developmentally regulated
alternative splicing of a 31-amino acid long "inter-repeat:repeat
module," raising the possibility that different MAP isoforms may
possess some distinct functional capabilities. Consistent with this
hypothesis, regulatory mutations in the human tau gene that disrupt the
normal balance between 3-repeat and 4-repeat tau isoform expression
lead to a collection of neurodegenerative diseases known as FTDP-17
(fronto-temporal dementias and Parkinsonism linked to chromosome 17),
which are characterized by the formation of pathological tau filaments
and neuronal cell death. Unfortunately, very little is known regarding structural and functional differences between the isoforms. In our
previous analyses, we focused on 4-repeat tau structure and function.
Here, we investigate 3-repeat tau, generating a series of truncations,
amino acid substitutions, and internal deletions and examining the
functional consequences. 3-Repeat tau possesses a "core microtubule
binding domain" composed of its first two repeats and the intervening
inter-repeat. This observation is in marked contrast to the widely held
notion that tau possesses multiple independent tubulin-binding sites
aligned in sequence along the length of the protein. In addition, we
observed that the carboxyl-terminal sequences downstream of the repeat
region make a strong but indirect contribution to microtubule binding activity in 3-repeat tau, which is in contrast to the negligible effect
of these same sequences in 4-repeat tau. Taken together with previous
work, these data suggest that 3-repeat and 4-repeat tau assume complex
and distinct structures that are regulated differentially, which in
turn suggests that they may possess isoform-specific functional
capabilities. The relevance of isoform-specific structure and function
to normal tau action and the onset of neurodegenerative disease are discussed.
Structural and Functional Differences between 3-Repeat and
4-Repeat Tau Isoforms
IMPLICATIONS FOR NORMAL TAU FUNCTION AND THE ONSET OF
NEURODEGENERATIVE DISEASE*
,
*
This work was supported by National Institutes of Health
Grant RO1 NS35010 (to S. C. F.), the California Department of Health Services, Alzheimer's Disease Program Grant 15716, and a National Research Service award fellowship (to M. C.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Present address: Dept. of Biology, Brandeis University, Waltham, MA.
§
Present address: DAKO Corp., Carpinteria, CA.
¶
Present address: AMGEN, Inc., Thousand Oaks, CA.
To whom correspondence should be addressed: Neuroscience
Research Institute and Dept. of Molecular, Cellular, and Developmental Biology, University of California, Santa Barbara, CA 93106. Tel.: 805-893-2659; Fax: 805-893-2005; E-mail:
feinstei@lifesci.ucsb.edu.
Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.
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