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PMID: 9190213 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S. Research Support, U.S. Gov't, P.H.S.

Functional interactions between the proline-rich and repeat regions of tau enhance microtubule binding and assembly.

Molecular biology of the cell ·Vol. 8 ·No. 2 ·1997-02-00 ·Pages 353-65

Goode BL, Denis PE, Panda D, Radeke MJ, Miller HP, Wilson L, Feinstein SC

Abstract

Tau is a neuronal microtubule-associated protein that promotes microtubule assembly, stability, and bundling in axons. Two distinct regions of tau are important for the tau-microtubule interaction, a relatively well-characterized "repeat region" in the carboxyl terminus (containing either three or four imperfect 18-amino acid repeats separated by 13- or 14-amino acid long inter-repeats) and a more centrally located, relatively poorly characterized proline-rich region. By using amino-terminal truncation analyses of tau, we have localized the microtubule binding activity of the proline-rich region to Lys215-Asn246 and identified a small sequence within this region, 215KKVAVVR221, that exerts a strong influence on microtubule binding and assembly in both three- and four-repeat tau isoforms. Site-directed mutagenesis experiments indicate that these capabilities are derived largely from Lys215/Lys216 and Arg221. In marked contrast to synthetic peptides corresponding to the repeat region, peptides corresponding to Lys215-Asn246 and Lys215-Thr222 alone possess little or no ability to promote microtubule assembly, and the peptide Lys215-Thr222 does not effectively suppress in vitro microtubule dynamics. However, combining the proline-rich region sequences (Lys215-Asn246) with their adjacent repeat region sequences within a single peptide (Lys215-Lys272) enhances microtubule assembly by 10-fold, suggesting intramolecular interactions between the proline-rich and repeat regions. Structural complexity in this region of tau also is suggested by sequential amino-terminal deletions through the proline-rich and repeat regions, which reveal an unusual pattern of loss and gain of function. Thus, these data lead to a model in which efficient microtubule binding and assembly activities by tau require intramolecular interactions between its repeat and proline-rich regions. This model, invoking structural complexity for the microtubule-bound conformation of tau, is fundamentally different from previous models of tau structure and function, which viewed tau as a simple linear array of independently acting tubulin-binding sites.

MeSH Terms
Amino Acid Sequence Asparagine Binding Sites Lysine Microtubules/metabolism,physiology Molecular Sequence Data Peptides/chemical synthesis,chemistry,metabolism Proline/metabolism Proline-Rich Protein Domains Structure-Activity Relationship tau Proteins/chemistry,metabolism
Chemicals
Peptides tau Proteins Asparagine Proline Lysine
Authors & Affiliations
7 authors, click to expand affiliations / ORCID
Goode B L
Department of Molecular, Cellular, and Developmental Biology, University of California, Santa Barbara 93106, USA.
Denis P E
Panda D
Radeke M J
Miller H P
Wilson L
Feinstein S C
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Article Info
Journal
Molecular biology of the cell
Abbr.
Mol Biol Cell
ISSN
1059-1524
DOI
10.1091/mbc.8.2.353
Published
1997-02-00
Pages
353-65
Language
English
Region
United States
NLM ID
9201390
PMCID
PMC276085
Subset
IM
Grants
NINDS NIH HHS · NS13560 · United States
NINDS NIH HHS · NS35010 · United States
External Links
PubMed source DOI: 10.1091/mbc.8.2.353 PMC Full Text View journal details
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