DOI: 10.1042/bst0360157. The effects of conformational heterogeneity on the binding of the Notch intracellular domain to effector proteins: a case of biologically tuned disorder

The effects of conformational heterogeneity on the binding of the Notch intracellular domain to effector proteins: a case of biologically tuned disorder

10.1042/bst0360157

Crossref journal-article

Portland Press Ltd.

Biochemical Society Transactions (288)

Abstract

Cell-fate decisions in metazoans are frequently guided by the Notch signalling pathway. Notch signalling is orchestrated by a type-1 transmembrane protein, which, upon interacting with extracellular ligands, is proteolytically cleaved to liberate a large intracellular domain [NICD (Notch intracellular domain)]. NICD enters the nucleus where it binds the transcription factor CSL (CBF1/suppressor of Hairless/Lag-1) and activates transcription of Notch-responsive genes. In the present paper, the interaction between the Drosophila NICD and CSL will be examined. This interaction involves two separate binding regions on NICD: the N-terminal tip of NICD {the RAM [RBP-Jκ (recombination signal-binding protein 1 for Jκ)-associated molecule] region} and an ankyrin domain ∼100 residues away. CD studies show that the RAM region of NICD lacks α-helical and β-sheet secondary structure, and also lacks rigid tertiary structure. Fluorescence studies show that the tryptophan residues in RAM are highly solvated and are quenched by solvent. To assess the impact of this apparent disorder on the bivalent binding of NICD to CSL, we modelled the region between the RAM and ANK (ankyrin repeat)-binding regions using polymer statistics. A WLC (wormlike chain) model shows that the most probable sequence separation between the two binding regions is ∼50 Å (1 Å=0.1 nm), matching the separation between these two sites in the complex. The WLC model predicts a substantial enhancement of ANK occupancy via effective concentration, and suggests that the linker length between the two binding regions is optimal for bivalent interaction.

Bibliography

Bertagna, A., Toptygin, D., Brand, L., & Barrick, D. (2008). The effects of conformational heterogeneity on the binding of the Notch intracellular domain to effector proteins: a case of biologically tuned disorder. Biochemical Society Transactions, 36(2), 157â166.

Authors 4

Angela Bertagna (first)
Dima Toptygin (additional)
Ludwig Brand (additional)
Doug Barrick (additional)

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Dates

Type	When
Created	17 years, 5 months ago (March 31, 2008, 8:14 a.m.)
Deposited	3 years, 9 months ago (Nov. 18, 2021, 6 p.m.)
Indexed	1 month, 1 week ago (July 26, 2025, 5:25 a.m.)
Issued	17 years, 5 months ago (March 20, 2008)
Published	17 years, 5 months ago (March 20, 2008)
Published Online	17 years, 5 months ago (March 20, 2008)
Published Print	17 years, 5 months ago (April 1, 2008)

Funders 0

None

BibTeX

@article{Bertagna_2008, title={The effects of conformational heterogeneity on the binding of the Notch intracellular domain to effector proteins: a case of biologically tuned disorder}, volume={36}, ISSN={1470-8752}, url={http://dx.doi.org/10.1042/bst0360157}, DOI={10.1042/bst0360157}, number={2}, journal={Biochemical Society Transactions}, publisher={Portland Press Ltd.}, author={Bertagna, Angela and Toptygin, Dima and Brand, Ludwig and Barrick, Doug}, year={2008}, month=mar, pages={157–166} }

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