Active fragments from pro- and antiapoptotic BCL-2 proteins have distinct membrane behavior reflecting their functional divergence.
BACKGROUND
The BCL-2 family of proteins includes pro- and antiapoptotic members acting by controlling the permeabilization of mitochondria. Although the association of these proteins with the outer mitochondrial membrane is crucial for their function, little is known about the characteristics of this interaction.


RESULTS
Here, we followed a reductionist approach to clarify to what extent membrane-active regions of homologous BCL-2 family proteins contribute to their functional divergence. Using isolated mitochondria as well as model lipid Langmuir monolayers coupled with Brewster Angle Microscopy, we explored systematically and comparatively the membrane activity and membrane-peptide interactions of fragments derived from the central helical hairpin of BAX, BCL-xL and BID. The results show a connection between the differing abilities of the assayed peptide fragments to contact, insert, destabilize and porate membranes and the activity of their cognate proteins in programmed cell death.


CONCLUSIONS
BCL-2 family-derived pore-forming helices thus represent structurally analogous, but functionally dissimilar membrane domains.
Guillemin
Yannis
Y
Institut de Biologie et Chimie des Protéines (IBCP), CNRS UMR5086, University of Lyon, Lyon, France.
Lopez
Jonathan
J
Gimenez
Diana
D
Fuertes
Gustavo
G
Valero
Juan Garcia
JG
Blum
Loïc
L
Gonzalo
Philippe
P
Salgado
Jesùs
J
Girard-Egrot
Agnès
A
Aouacheria
Abdel
A
D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis; D051023:BH3 Interacting Domain Death Agonist Protein / Q000737:chemistry* / Q000378:metabolism; D002460:Cell Line; D045304:Cytochromes c / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008051:Lipid Bilayers / Q000737:chemistry / Q000378:metabolism; D008563:Membrane Lipids / Q000737:chemistry* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008853:Microscopy / Q000379:methods; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D011485:Protein Binding; D017386:Sequence Homology, Amino Acid; D051028:bcl-2-Associated X Protein / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D051020:bcl-X Protein / Q000737:chemistry* / Q000378:metabolism
D051023:BH3 Interacting Domain Death Agonist Protein; D008051:Lipid Bilayers; D008563:Membrane Lipids; D010446:Peptide Fragments; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein; D045304:Cytochromes c