PDBsum entry 5miu

Oxidoreductase

PDB id: 5miu

Contents

Protein chains

453 a.a.

Ligands

FAD ×2

Waters ×25

References listed in PDB file

Key reference

• Title: Structural bases of the altered catalytic properties of a pathogenic variant of apoptosis inducing factor.
• Authors: L.Sorrentino, F.Cossu, M.Milani, A.Aliverti, E.Mastrangelo.
• Ref.: Biochem Biophys Res Commun, 2017, 490, 1011-1017. [DOI no: 10.1016/j.bbrc.2017.06.156]
• PubMed id: 28666871

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^CT) 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.