C-terminal residues regulate localization and function of the antiapoptotic protein Bfl-1.
Unlike other antiapoptotic members of the Bcl-2 family, Bfl-1 does not contain a well defined C-terminal transmembrane domain, and whether the C-terminal tail of Bfl-1 functions as a membrane anchor is not yet clearly established. The molecular modeling study of the full-length Bfl-1 performed within this work suggests that Bfl-1 may co-exist in two distinct conformational states: one in which its C-terminal helix alpha9 is inserted in the hydrophobic groove formed by the BH1-3 domains of Bfl-1 and one with its C terminus. Parallel analysis of the subcellular localization of Bfl-1 indicates that even if Bfl-1 may co-exist in two distinct conformational states, most of the endogenous protein is tightly associated with the mitochondria by its C terminus in both healthy and apoptotic peripheral blood lymphocytes as well as in malignant B cell lines. However, the helix alpha9 of Bfl-1, and therefore the binding of Bfl-1 to mitochondria, is not absolutely required for the antiapoptotic activity of Bfl-1. A particular feature of Bfl-1 is the amphipathic character of its C-terminal helix alpha9. Our data clearly indicate that this property of helix alpha9 is required for the anchorage of Bfl-1 to the mitochondria but also regulates the antiapoptotic function Bfl-1.
Brien
Gaelle
G
INSERM, U851, Lyon F-69007, France.
Debaud
Anne-Laure
AL
Robert
Xavier
X
Oliver
Lisa
L
Trescol-Biemont
Marie-Claude
MC
Cauquil
Nicolas
N
Geneste
Olivier
O
Aghajari
Nushin
N
Vallette
Francois M
FM
Haser
Richard
R
Bonnefoy-Berard
Nathalie
N
D000596:Amino Acids; D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins; D001402:B-Lymphocytes / Q000473:pathology; D002460:Cell Line; D045744:Cell Line, Tumor; D006801:Humans; D008214:Lymphocytes / Q000166:cytology; D051379:Mice; D015778:Minor Histocompatibility Antigens; D008928:Mitochondria / Q000378:metabolism*; D008958:Models, Molecular; D011485:Protein Binding; D011487:Protein Conformation; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*
D000596:Amino Acids; D051017:Apoptosis Regulatory Proteins; C096816:BCL2-related protein A1; D015778:Minor Histocompatibility Antigens; D019253:Proto-Oncogene Proteins c-bcl-2