PDBsum entry 5miu

Oxidoreductase

PDB id: 5miu

Contents

Protein chains

453 a.a.

Ligands

FAD ×2

Waters ×25

PDB id:

5miu

Name:

Oxidoreductase

Title:

G307e variant of murine apoptosis inducing factor (oxidized state)

Structure:

Apoptosis-inducing factor 1, mitochondrial. Chain: a, b. Synonym: programmed cell death protein 8. Engineered: yes

Source:

Mus musculus. Mouse. Organism_taxid: 10090. Gene: aifm1, aif, pdcd8. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008

Resolution:

3.50Å R-factor: 0.215 R-free: 0.279

Authors:

L.Sorrentino,F.Cossu,M.Milani,A.Aliverti,E.Mastrangelo

Key ref:

L.Sorrentino et al. (2017). Structural bases of the altered catalytic properties of a pathogenic variant of apoptosis inducing factor. Biochem Biophys Res Commun, 490, 1011-1017. PubMed id: 28666871 DOI: 10.1016/j.bbrc.2017.06.156

Date:

29-Nov-16 Release date: 12-Jul-17

Protein chains

Q9Z0X1  (AIFM1_MOUSE) -  Apoptosis-inducing factor 1, mitochondrial from Mus musculus

Seq: 612 a.a.

Struc: 453 a.a.*

* PDB and UniProt seqs differ at 1 residue position (black cross)

Enzyme reactions

• Enzyme class: E.C.1.6.99.- - ?????

DOI no: 10.1016/j.bbrc.2017.06.156

Biochem Biophys Res Commun 490:1011-1017 (2017)

PubMed id: 28666871

Structural bases of the altered catalytic properties of a pathogenic variant of apoptosis inducing factor.

L.Sorrentino, F.Cossu, M.Milani, A.Aliverti, E.Mastrangelo.

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.