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Two C-terminal ankyrin repeats form the minimal stable unit of the ankyrin repeat protein p18INK4c

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Abstract

Ankyrin repeat proteins (ARPs) appear to be abundant in organisms from all phyla, and play critical regulatory roles, mediating specific interactions with target biomolecules and thus ordering the sequence of events in diverse cellular processes. ARPs possess a non-globular scaffold consisting of repeating motifs named ankyrin (ANK) repeats, which stack on each other. The modular architecture of ARPs provides a new paradigm for understanding protein stability and folding mechanisms. In the present study, the stability of various C-terminal fragments of the ARP p18INK4c was investigated by all-atomic 450 ns molecular dynamics (MD) simulations in explicit water solvent. Only motifs with at least two ANK repeats made stable systems in the available timescale. All smaller fragments were unstable, readily losing their native fold and α-helical content. Since each non-terminal ANK repeat has two hydrophobic sides, we may hypothesize that at least one hydrophobic side must be fully covered and shielded from the water as a necessary, but not sufficient, condition to maintain ANK repeat stability. Consequently, at least two ANK repeats are required to make a stable ARP.

Structure of the p18INK4c protein (PDB entry 1IHB, chain B), which is a member of the cyclin-dependent kinase inhibitor (INK) tumor suppressor family with five ankyrin (ANK) repeat modules. The figure was generated by PyMol http://pymol.sourceforge.net/

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Acknowledgments

Support through the MSMT (Ministry of Youths, Sports and Education, Czech Republic) grants LC512 and MSM6198959216 is gratefully acknowledged. We thank Sees-Editing, Ltd., (UK) for language revision.

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Authors and Affiliations

  1. Department of Physical Chemistry and Center for Biomolecules and Complex Molecular Systems, Faculty of Science, Palacký University, tr. Svobody 26, 771 46, Olomouc, Czech Republic

    Petr Sklenovský, Pavel Banáš & Michal Otyepka

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  1. Petr Sklenovský
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  2. Pavel Banáš
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  3. Michal Otyepka
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Corresponding author

Correspondence to Michal Otyepka.

Electronic supplementary material

The supplementary material contains the time evolution charts of RMSD, R g, percentage of saved native contacts and α-helical content for all studied fragments.

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Sklenovský, P., Banáš, P. & Otyepka, M. Two C-terminal ankyrin repeats form the minimal stable unit of the ankyrin repeat protein p18INK4c . J Mol Model 14, 747–759 (2008). https://doi.org/10.1007/s00894-008-0300-5

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  • DOI: https://doi.org/10.1007/s00894-008-0300-5

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