Chemically synthesized human survivin does not inhibit caspase-3.
Survivin is a member of the inhibitor of apoptosis protein (IAP) family that blocks cell death by inhibiting the caspase activation pathways. Overexpressed in all common human neoplasms but undetectable in most normal adult tissues, survivin confers tumor resistance to apoptosis and represents an ideal molecular target for therapeutic intervention. How survivin blocks apoptosis, however, has been a subject of intense debate, as evidenced by conflicting reports regarding whether or not survivin can directly bind and inactivate effector caspases. We chemically synthesized large amounts of highly pure human survivin of 142 amino acid residues using native chemical ligation and functionally compared synthetic survivin and a recombinant XIAP--the most intensively studied member of the IAP family. Inhibition assays showed that, while caspase-3 could be effectively inhibited by XIAP, survivin had no detectable inhibitory activity against the enzyme, even at concentrations several thousand-fold higher than XIAP. Our finding supports the premise that survivin does not directly inhibit effector caspases.
Institute of Human Virology, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA.
Changqing
C
Li
Zhibin
Z
Wu
Min
M
Liu
Marzena
M
Pazgier
Wuyuan
W
Lu
D000595:Amino Acid Sequence; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D002021:Buffers; D053148:Caspase 3 / Q000032:analysis / Q000378:metabolism*; D016923:Cell Death / Q000187:drug effects; D019281:Dimerization; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D008869:Microtubule-Associated Proteins / Q000138:chemical synthesis* / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism* / Q000494:pharmacology; D008969:Molecular Sequence Data; D008970:Molecular Weight; D009363:Neoplasm Proteins / Q000138:chemical synthesis* / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism* / Q000494:pharmacology; D010446:Peptide Fragments / Q000138:chemical synthesis* / Q000737:chemistry; D011487:Protein Conformation; D017510:Protein Folding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000378:metabolism / Q000494:pharmacology; D012996:Solutions / Q000737:chemistry; D000077022:Survivin; D014867:Water / Q000737:chemistry; D015032:Zinc / Q000737:chemistry
C107489:BIRC5 protein, human; D002021:Buffers; D004791:Enzyme Inhibitors; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D010446:Peptide Fragments; D011994:Recombinant Proteins; D012996:Solutions; D000077022:Survivin; D014867:Water; D053148:Caspase 3; D015032:Zinc