Completing the family portrait of the anti-apoptotic Bcl-2 proteins: Crystal structure of human Bfl-1 in complex with Bim

Herman, Maria Dolores; Nyman, Tomas; Welin, Martin; Lehtiö, Lari; Flodin, Susanne; Trésaugues, Lionel; Kotenyova, Tetyana; Flores, Alex; Nordlund, Pär

doi:10.1016/j.febslet.2008.09.028

« Previous Next »FEBS Letters
Volume 582, Issue 25 , Pages 3590-3594, 29 October 2008

Completing the family portrait of the anti-apoptotic Bcl-2 proteins: Crystal structure of human Bfl-1 in complex with Bim

Edited by Irmgard Sinning

Maria Dolores Herman
- Division of Biophysics, Department of Medical Biochemistry and Biophysics, Karolinska Institute, Pär Nordlund, Nobels väg 5, 17177 Stockholm, Sweden
- Department of Biochemistry and Biophysics, Stockholm University, S-106 91 Stockholm, Sweden
- These authors contributed equally to this work.
Tomas Nyman
- Structural Genomics Consortium, Department of Medical Biochemistry and Biophysics, Karolinska Institute, 17177 Stockholm, Sweden
- These authors contributed equally to this work.
Martin Welin
- Structural Genomics Consortium, Department of Medical Biochemistry and Biophysics, Karolinska Institute, 17177 Stockholm, Sweden
Lari Lehtiö
- Structural Genomics Consortium, Department of Medical Biochemistry and Biophysics, Karolinska Institute, 17177 Stockholm, Sweden
Susanne Flodin
- Structural Genomics Consortium, Department of Medical Biochemistry and Biophysics, Karolinska Institute, 17177 Stockholm, Sweden
Lionel Trésaugues
- Structural Genomics Consortium, Department of Medical Biochemistry and Biophysics, Karolinska Institute, 17177 Stockholm, Sweden
Tetyana Kotenyova
- Structural Genomics Consortium, Department of Medical Biochemistry and Biophysics, Karolinska Institute, 17177 Stockholm, Sweden
Alex Flores
- Structural Genomics Consortium, Department of Medical Biochemistry and Biophysics, Karolinska Institute, 17177 Stockholm, Sweden
Pär Nordlund
- Structural Genomics Consortium, Department of Medical Biochemistry and Biophysics, Karolinska Institute, 17177 Stockholm, Sweden
- Division of Biophysics, Department of Medical Biochemistry and Biophysics, Karolinska Institute, Pär Nordlund, Nobels väg 5, 17177 Stockholm, Sweden
- Corresponding author. Address: Structural Genomics Consortium, Department of Medical Biochemistry and Biophysics, Karolinska Institute, 17177 Stockholm, Sweden. Fax: +46 852486850.

Received 21 May 2008; received in revised form 20 August 2008; accepted 2 September 2008. published online 22 September 2008.

Abstract

Evasion of apoptosis is recognized as a characteristic of malignant growth. Anti-apoptotic B-cell lymphoma-2 (Bcl-2) family members have therefore emerged as potential therapeutic targets due to their critical role in proliferating cancer cells. Here, we present the crystal structure of Bfl-1, the last anti-apoptotic Bcl-2 family member to be structurally characterized, in complex with a peptide corresponding to the BH3 region of the pro-apoptotic protein Bim. The structure reveals distinct features at the peptide-binding site, likely to define the binding specificity for pro-apoptotic proteins. Superposition of the Bfl-1:Bim complex with that of Mcl-1:Bim reveals a significant local plasticity of hydrophobic interactions contributed by the Bim peptide, likely to be the basis for the multi specificity of Bim for anti-apoptotic proteins.

Abbreviations: Bcl-2, B-cell lymphoma-2, BH, Bcl-2 homology motif

Keywords: Apoptosis, B-cell lymphoma-2, Cancer, Bfl-1, A1, Crystal structure