A splicing variant of the Bcl-2 member Bok with a truncated BH3 domain induces apoptosis but does not dimerize with antiapoptotic Bcl-2 proteins in vitro.
Bok (Bcl-2-related ovarian killer) is a proapoptotic Bcl-2 family protein identified in the ovary based on its dimerization with the antiapoptotic protein Mcl-1. In addition to the Bcl-2 homology (BH) domains 1 and 2 and the transmembrane sequence, Bok also has a BH3 domain believed to be important for dimerization with selective antiapoptotic Bcl-2 proteins and cell killing. We identified a splicing variant of Bok mRNA with a deletion of 43 residues from the full-length protein (Bok-L), leading to the fusion of the N-terminal-half of its BH3 domain to the C-terminal-half of the BH1 domain. Genomic analysis indicated that the Bok has five exons, and the short form of Bok (Bok-S) represents the splicing out of exon three during transcription. Although Bok-S retains the apoptosis-inducing activity in transfected cells, it has lost the ability to dimerize with antiapoptotic proteins in vitro. Additional BH3 domain mutations of Bok-L also led to defective heterodimerization without affecting its proapoptotic action. Furthermore, similar deletions for the related channel-forming proapoptotic Bax and Bak did not impair their cell killing ability. Thus, the naturally occurring Bok-S variant represents a new form of proapoptotic protein that induces cell killing without heterodimerization with antiapoptotic Bcl-2 proteins. This variant appears to contain the minimal module spanning BH1 and BH2 domains and the transmembrane sequence for apoptosis induction by channel-forming Bcl-2 proteins.
Hsu
S Y
SY
Division of Reproductive Biology, Department of Gynecology and Obstetrics, Stanford University Medical School, Stanford, California 94305-5317, USA.
Hsueh
A J
AJ
D017398:Alternative Splicing; D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001665:Binding Sites; D002352:Carrier Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D019281:Dimerization; D005260:Female; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008954:Models, Biological; D008969:Molecular Sequence Data; D010053:Ovary / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D014162:Transfection; D014599:Uterus / Q000378:metabolism; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein
C494773:Bak1 protein, mouse; C494774:Bak1 protein, rat; C494827:Bax protein, mouse; C494828:Bax protein, rat; D002352:Carrier Proteins; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein