5MIU

G307E variant of Murine Apoptosis Inducing Factor (oxidized state)

5MIU の概要

• エントリーDOI: 10.2210/pdb5miu/pdb
• 分子名称: Apoptosis-inducing factor 1, mitochondrial, FLAVIN-ADENINE DINUCLEOTIDE (3 entities in total)
• 機能のキーワード: apoptosis inducing factor oxidoreductase, oxidoreductase
• 由来する生物種: Mus musculus (Mouse)
• 細胞内の位置: Mitochondrion intermembrane space : Q9Z0X1
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 118371.63

構造登録者

Sorrentino, L.,Cossu, F.,Milani, M.,Aliverti, A.,Mastrangelo, E. (登録日: 2016-11-29, 公開日: 2017-07-12, 最終更新日: 2024-01-17)

主引用文献

Sorrentino, L.,Cossu, F.,Milani, M.,Aliverti, A.,Mastrangelo, E.
Structural bases of the altered catalytic properties of a pathogenic variant of apoptosis inducing factor.
Biochem. Biophys. Res. Commun., 490:1011-1017, 2017

PubMed Abstract: The apoptosis-inducing factor (AIF) is a FAD-containing protein playing critical roles in caspase-independent apoptosis and mitochondrial respiratory chain biogenesis and maintenance. While its lethal role is well known, the details of its mitochondrial function remain elusive. So far, nineteen allelic variants of AIF have been associated to human diseases, mainly affecting the nervous system. A strict correlation is emerging between the degree of impairment of its ability to stabilize the charge-transfer (CT) complex between FAD and NAD and the severity of the resulting pathology. Recently, we demonstrated that the G307E replacement in murine AIF (equivalent to the pathogenic G308E in the human protein) dramatically decreases the rate of CT complex formation through the destabilization of the flavoprotein interaction with NAD(H). To provide further insights into the structural bases of its altered functional properties, here we report the first crystal structure of an AIF pathogenic mutant variant in complex with NAD (murine AIF-G307E) in comparison with its oxidized form. With respect to wild type AIF, the mutation leads to an altered positioning of NAD adenylate moiety, which slows down CT complex formation. Moreover, the altered balance between the binding of the adenine/nicotinamide portions of the coenzyme determines a large drop in AIF-G307E ability to discriminate between NADH and NADPH.

PubMed: 28666871
DOI: 10.1016/j.bbrc.2017.06.156

実験手法

X-RAY DIFFRACTION (3.5 Å)