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Title: Ankyrin repeats as a dimerization module

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Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
OSTI Identifier:
Resource Type:
Journal Article
Resource Relation:
Journal Name: Biochemical and Biophysical Research Communications; Journal Volume: 495; Journal Issue: 1
Country of Publication:
United States

Citation Formats

Kozlov, Guennadi, Wong, Kathy, Wang, Wenxuan, Skubák, Pavol, Muñoz-Escobar, Juliana, Liu, Yue, Siddiqui, Nadeem, Pannu, Navraj S., and Gehring, Kalle. Ankyrin repeats as a dimerization module. United States: N. p., 2018. Web. doi:10.1016/j.bbrc.2017.11.135.
Kozlov, Guennadi, Wong, Kathy, Wang, Wenxuan, Skubák, Pavol, Muñoz-Escobar, Juliana, Liu, Yue, Siddiqui, Nadeem, Pannu, Navraj S., & Gehring, Kalle. Ankyrin repeats as a dimerization module. United States. doi:10.1016/j.bbrc.2017.11.135.
Kozlov, Guennadi, Wong, Kathy, Wang, Wenxuan, Skubák, Pavol, Muñoz-Escobar, Juliana, Liu, Yue, Siddiqui, Nadeem, Pannu, Navraj S., and Gehring, Kalle. 2018. "Ankyrin repeats as a dimerization module". United States. doi:10.1016/j.bbrc.2017.11.135.
title = {Ankyrin repeats as a dimerization module},
author = {Kozlov, Guennadi and Wong, Kathy and Wang, Wenxuan and Skubák, Pavol and Muñoz-Escobar, Juliana and Liu, Yue and Siddiqui, Nadeem and Pannu, Navraj S. and Gehring, Kalle},
abstractNote = {},
doi = {10.1016/j.bbrc.2017.11.135},
journal = {Biochemical and Biophysical Research Communications},
number = 1,
volume = 495,
place = {United States},
year = 2018,
month = 1
  • Folding and stability of proteins containing ankyrin repeats (ARs) is of great interest because they mediate numerous protein-protein interactions involved in a wide range of regulatory cellular processes. Notch, an ankyrin domain containing protein, signals by converting a transcriptional repression complex into an activation complex. The Notch ANK domain is essential for Notch function and contains seven ARs. Here, we present the 2.2 {angstrom} crystal structure of ARs 4-7 from mouse Notch 1 (m1ANK). These C-terminal repeats were resistant to degradation during crystallization, and their secondary and tertiary structures are maintained in the absence of repeats 1-3. The crystallized fragmentmore » adopts a typical ankyrin fold including the poorly conserved seventh AR, as seen in the Drosophila Notch ANK domain (dANK). The structural preservation and stability of the C-terminal repeats shed a new light onto the mechanism of hetero-oligomeric assembly during Notch-mediated transcriptional activation.« less
  • Spectrin and ankyrin participate in membrane organization, stability, signal transduction, and protein targeting; their interaction is critical for erythrocyte stability. Repeats 14 and 15 of {beta}I-spectrin are crucial for ankyrin recognition, yet the way spectrin binds ankyrin while preserving its repeat structure is unknown. We have solved the crystal structure of the {beta}I-spectrin 14,15 di-repeat unit to 2.1 {angstrom} resolution and found 14 residues critical for ankyrin binding that map to the end of the helix C of repeat 14, the linker region, and the B-C loop of repeat 15. The tilt (64{sup o}) across the 14,15 linker is greatermore » than in any published di-repeat structure, suggesting that the relative positioning of the two repeats is important for ankyrin binding. We propose that a lack of structural constraints on linker and inter-helix loops allows proteins containing spectrin-like di-repeats to evolve diverse but specific ligand-recognition sites without compromising the structure of the repeat unit. The linker regions between repeats are thus critical determinants of both spectrin's flexibility and polyfunctionality. The putative coupling of flexibility and ligand binding suggests a mechanism by which spectrin might participate in mechanosensory regulation.« less
  • Histone modifications have important roles in transcriptional control, mitosis and heterochromatin formation. G9a and G9a-like protein (GLP) are euchromatin-associated methyltransferases that repress transcription by mono- and dimethylating histone H3 at Lys9 (H3K9). Here we demonstrate that the ankyrin repeat domains of G9a and GLP bind with strong preference to N-terminal H3 peptides containing mono- or dimethyl K9. X-ray crystallography revealed the basis for recognition of the methylated lysine by a partial hydrophobic cage with three tryptophans and one acidic residue. Substitution of key residues in the cage eliminated the H3 tail interaction. Hence, G9a and GLP contain a new typemore » of methyllysine binding module (the ankyrin repeat domains) and are the first examples of protein (histone) methyltransferases harboring in a single polypeptide the activities that generate and read the same epigenetic mark.« less
  • On the basis of tissue-specific enzyme activity and inhibition by catalytic products, Hans Krebs first demonstrated the existence of multiple glutaminases in mammals. Currently, two human genes are known to encode at least four glutaminase isoforms. But, the phylogeny of these medically relevant enzymes remains unclear, prompting us to investigate their origin and evolution. Using prokaryotic and eukaryotic glutaminase sequences, we built a phylogenetic tree whose topology suggested that the multidomain architecture was inherited from bacterial ancestors, probably simultaneously with the hosting of the proto-mitochondrion endosymbiont. We propose an evolutionary model wherein the appearance of the most active enzyme isoform,more » glutaminase C (GAC), which is expressed in many cancers, was a late retrotransposition event that occurred in fishes from the Chondrichthyes class. The ankyrin (ANK) repeats in the glutaminases were acquired early in their evolution. In order to obtain information on ANK folding, we solved two high-resolution structures of the ANK repeat-containing C termini of both kidney-type glutaminase (KGA) and GLS2 isoforms (glutaminase B and liver-type glutaminase). We also found that the glutaminase ANK repeats form unique intramolecular contacts through two highly conserved motifs; curiously, this arrangement occludes a region usually involved in ANK-mediated protein-protein interactions. We also solved the crystal structure of full-length KGA and present a small-angle X-ray scattering model for full-length GLS2. These structures explain these proteins' compromised ability to assemble into catalytically active supra-tetrameric filaments, as previously shown for GAC. Collectively, these results provide information about glutaminases that may aid in the design of isoform-specific glutaminase inhibitors.« less