DOI: 10.1110/ps.03279003. Structure and stability of the ankyrin domain of the <i>Drosophila</i> Notch receptor

Structure and stability of the ankyrin domain of the Drosophila Notch receptor

10.1110/ps.03279003

Crossref journal-article

Wiley

Protein Science (311)

Abstract

AbstractThe Notch receptor contains a conserved ankyrin repeat domain that is required for Notch‐mediated signal transduction. The ankyrin domain of Drosophila Notch contains six ankyrin sequence repeats previously identified as closely matching the ankyrin repeat consensus sequence, and a putative seventh C‐terminal sequence repeat that exhibits lower similarity to the consensus sequence. To better understand the role of the Notch ankyrin domain in Notch‐mediated signaling and to examine how structure is distributed among the seven ankyrin sequence repeats, we have determined the crystal structure of this domain to 2.0 Å resolution. The seventh, C‐terminal, ankyrin sequence repeat adopts a regular ankyrin fold, but the first, N‐terminal ankyrin repeat, which contains a 15‐residue insertion, appears to be largely disordered. The structure reveals a substantial interface between ankyrin polypeptides, showing a high degree of shape and charge complementarity, which may be related to homotypic interactions suggested from indirect studies. However, the Notch ankyrin domain remains largely monomeric in solution, demonstrating that this interface alone is not sufficient to promote tight association. Using the structure, we have classified reported mutations within the Notch ankyrin domain that are known to disrupt signaling into those that affect buried residues and those restricted to surface residues. We show that the buried substitutions greatly decrease protein stability, whereas the surface substitutions have only a marginal affect on stability. The surface substitutions are thus likely to interfere with Notch signaling by disrupting specific Notch‐effector interactions and map the sites of these interactions.

Bibliography

Zweifel, M. E., Leahy, D. J., Hughson, F. M., & Barrick, D. (2003). Structure and stability of the ankyrin domain of the Drosophila Notch receptor. Protein Science, 12(11), 2622â2632. Portico.

Authors 4

Mark E. Zweifel (first)
Daniel J. Leahy (additional)
Frederick M. Hughson (additional)
Doug Barrick (additional)

References 61 Referenced 85

Dates

Type	When
Created	21 years, 10 months ago (Oct. 22, 2003, 3:41 p.m.)
Deposited	1 year, 10 months ago (Oct. 8, 2023, 9:53 a.m.)
Indexed	3 months, 2 weeks ago (May 21, 2025, 2:26 p.m.)
Issued	21 years, 10 months ago (Nov. 1, 2003)
Published	21 years, 10 months ago (Nov. 1, 2003)
Published Online	16 years, 8 months ago (Jan. 1, 2009)
Published Print	21 years, 10 months ago (Nov. 1, 2003)

Funders 0

None

BibTeX

@article{Zweifel_2003, title={Structure and stability of the ankyrin domain of the Drosophila Notch receptor}, volume={12}, ISSN={1469-896X}, url={http://dx.doi.org/10.1110/ps.03279003}, DOI={10.1110/ps.03279003}, number={11}, journal={Protein Science}, publisher={Wiley}, author={Zweifel, Mark E. and Leahy, Daniel J. and Hughson, Frederick M. and Barrick, Doug}, year={2003}, month=nov, pages={2622–2632} }

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  "abstract": "<jats:title>Abstract</jats:title><jats:p>The Notch receptor contains a conserved ankyrin repeat domain that is required for Notch\u2010mediated signal transduction. The ankyrin domain of <jats:italic>Drosophila</jats:italic> Notch contains six ankyrin sequence repeats previously identified as closely matching the ankyrin repeat consensus sequence, and a putative seventh C\u2010terminal sequence repeat that exhibits lower similarity to the consensus sequence. To better understand the role of the Notch ankyrin domain in Notch\u2010mediated signaling and to examine how structure is distributed among the seven ankyrin sequence repeats, we have determined the crystal structure of this domain to 2.0 \u00c5 resolution. The seventh, C\u2010terminal, ankyrin sequence repeat adopts a regular ankyrin fold, but the first, N\u2010terminal ankyrin repeat, which contains a 15\u2010residue insertion, appears to be largely disordered. The structure reveals a substantial interface between ankyrin polypeptides, showing a high degree of shape and charge complementarity, which may be related to homotypic interactions suggested from indirect studies. However, the Notch ankyrin domain remains largely monomeric in solution, demonstrating that this interface alone is not sufficient to promote tight association. Using the structure, we have classified reported mutations within the Notch ankyrin domain that are known to disrupt signaling into those that affect buried residues and those restricted to surface residues. We show that the buried substitutions greatly decrease protein stability, whereas the surface substitutions have only a marginal affect on stability. The surface substitutions are thus likely to interfere with Notch signaling by disrupting specific Notch\u2010effector interactions and map the sites of these interactions.</jats:p>",
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