Abstracts (complete list) - Wissenschaft Online

Josip Zovko, Marco Herold, Christa Kraus, Andrea Peters, Ingolf Berberich
Identification of proteins that influence stability and
functionality of the anti-apoptotic Bcl-2 family member A1/
Bfl-1
Members of the Bcl-2 family control the integrity of mitochondria and thereby influence
survival and death of cells. Most Bcl-2 family members can localize to intracellular
membranes via hydrophobic sequences within their C-terminal portion.
Murine A1 and its human homologue Bfl-1 are anti-apoptotic members of the Bcl-2
family. A1 is expressed in small amounts in the bone marrow and immature B cells, but
in high amounts in mature B cells. Thus the protein seems to be important for B cell
maturation.
We analyzed the function of the C-terminus of A1. Unless the C-terminal ends of other
Bcl-2 proteins the tail of A1 does not function as a membrane anchor. Nevertheless, the
last amino acids of A1 are important for the protein. In fact, the C-terminus of A1
serves a dual function by being required for the instability and the anti-apoptotic
potential of the protein. We show that A1 undergoes proteosomal degradation controlled
by its C-terminus. Interestingly, binding to the pro-apoptotic Bcl-2 factor BimEL results
in increased stability of A1. This is due to reduced ubiquitination of A1 after binding of
BimEL. We conclude that the C-terminus of A1/Bfl-1 serves as a docking site for E3
ubiquitin ligase(s) that control the stability of A1 by targeting the protein to the
proteasomal pathway. Currently, we are trying to identify such proteins by affinity
chromatography and mass spectrometry.