7UJV

Structure of PHD2 in complex with HIF2a-CODD

7UJV の概要

• エントリーDOI: 10.2210/pdb7ujv/pdb
• 分子名称: Egl nine homolog 1, Endothelial PAS domain-containing protein 1, N-OXALYLGLYCINE, ... (6 entities in total)
• 機能のキーワード: hif-prolyl-hydroxylase, complex, oxygen-sensing, psuedohypoxic-disease, oxidoreductase
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 30416.15

構造登録者

Ferens, F.G.,Tarade, D.,Lee, J.E.,Ohh, M. (登録日: 2022-03-31, 公開日: 2023-04-05, 最終更新日: 2024-11-13)

主引用文献

Ferens, F.G.,Taber, C.C.,Stuart, S.,Hubert, M.,Tarade, D.,Lee, J.E.,Ohh, M.
Deficiency in PHD2-mediated hydroxylation of HIF2 alpha underlies Pacak-Zhuang syndrome.
Commun Biol, 7:240-240, 2024

PubMed Abstract: Pacak-Zhuang syndrome is caused by mutations in the EPAS1 gene, which encodes for one of the three hypoxia-inducible factor alpha (HIFα) paralogs HIF2α and is associated with defined but varied phenotypic presentations including neuroendocrine tumors and polycythemia. However, the mechanisms underlying the complex genotype-phenotype correlations remain incompletely understood. Here, we devised a quantitative method for determining the dissociation constant (K) of the HIF2α peptides containing disease-associated mutations and the catalytic domain of prolyl-hydroxylase (PHD2) using microscale thermophoresis (MST) and showed that neuroendocrine-associated Class 1 HIF2α mutants have distinctly higher K than the exclusively polycythemia-associated Class 2 HIF2α mutants. Based on the co-crystal structure of PHD2/HIF2α peptide complex at 1.8 Å resolution, we showed that the Class 1 mutated residues are localized to the critical interface between HIF2α and PHD2, adjacent to the PHD2 active catalytic site, while Class 2 mutated residues are localized to the more flexible region of HIF2α that makes less contact with PHD2. Concordantly, Class 1 mutations were found to significantly increase HIF2α-mediated transcriptional activation in cellulo compared to Class 2 counterparts. These results reveal a structural mechanism in which the strength of the interaction between HIF2α and PHD2 is at the root of the general genotype-phenotype correlations observed in Pacak-Zhuang syndrome.

PubMed: 38418569
DOI: 10.1038/s42003-024-05904-4

実験手法

X-RAY DIFFRACTION (1.8 Å)