5U0J

C-terminal ankyrin repeats from human kidney-type glutaminase (KGA) - monoclinic crystal form

5U0J の概要

• エントリーDOI: 10.2210/pdb5u0j/pdb
• 関連するPDBエントリー: 5U0I 5U0K
• 分子名称: Glutaminase kidney isoform, mitochondrial, SODIUM ION (3 entities in total)
• 機能のキーワード: glutaminase, ankyrin, human, gls1, hydrolase
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 63372.80

構造登録者

Pasquali, C.C.,Gonzalez, A.,Dias, S.M.G.,Ambrosio, A.L.B. (登録日: 2016-11-24, 公開日: 2017-05-24, 最終更新日: 2023-10-04)

主引用文献

Pasquali, C.C.,Islam, Z.,Adamoski, D.,Ferreira, I.M.,Righeto, R.D.,Bettini, J.,Portugal, R.V.,Yue, W.W.,Gonzalez, A.,Dias, S.M.G.,Ambrosio, A.L.B.
The origin and evolution of human glutaminases and their atypical C-terminal ankyrin repeats.
J. Biol. Chem., 292:11572-11585, 2017

PubMed Abstract: 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. However, 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, 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. 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 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.

PubMed: 28526749
DOI: 10.1074/jbc.M117.787291

実験手法

X-RAY DIFFRACTION (1.72 Å)