The Anti-Apoptotic Bcl-xL Protein, a New Piece in the Puzzle of Cytochrome C Interactome

Pierandrea Temussi,Ivano Bertini,Soizic Chevance,Daniela Lalli,Paola Turano,Rebecca Del Conte

doi:10.1371/journal.pone.0018329

Pierandrea Temussi, Ivano Bertini + Show 4 more

Open Access

https://doi.org/10.1371/journal.pone.0018329

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Abstract

A structural model of the adduct between human cytochrome c and the human anti-apoptotic protein Bcl-xL, which defines the protein-protein interaction surface, was obtained from solution NMR chemical shift perturbation data. The atomic level information reveals key intermolecular contacts identifying new potentially druggable areas on cytochrome c and Bcl-xL. Involvement of residues on cytochrome c other than those in its complexes with electron transfer partners is apparent. Key differences in the contact area also exist between the Bcl-xL adduct with the Bak peptide and that with cytochrome c. The present model provides insights to the mechanism by which cytochrome c translocated to cytosol can be intercepted, so that the apoptosome is not assembled.

Highlights

Cytochrome c is a small soluble heme protein loosely associated with the inner membrane of the mitochondrion, where it acts as an electron carrier between the two terminal complexes of the respiration chain, cytochrome bc1 and cytochrome c oxidase [1], [2]
Upon extrusion into the cytosol, cytochrome c forms the apoptosome with Apaf-1 and pro-caspase-9, initiating the caspase cascade of reactions that leads to apoptosis [4]
It has been proposed to occur in two steps: the upstream event of cytochrome c dissociation from the inner membrane that renders it available for the subsequent release into the cytosol upon permeabilization of the outer mitochondrial by oligomeric pro-apoptotic members of the Bcl-2 family of proteins [5]

Summary

Introduction

Cytochrome c is a small soluble heme protein loosely associated with the inner membrane of the mitochondrion, where it acts as an electron carrier between the two terminal complexes of the respiration chain, cytochrome bc1 and cytochrome c oxidase [1], [2]. We report an NMR-derived model structure of human Bcl-xL in complex with human cytochrome c, in its iron(II) form that should represent the relevant redox state for heme iron in the reducing environment of the cytosol.

Results

Conclusion