Solution structure of human survivin and its binding interface with Smac/Diablo

Area of Science:

• Biochemistry
• Structural Biology
• Molecular Biology

Background:

• The antiapoptotic protein survivin plays a crucial role in cell survival and is a target in cancer therapy.
• Understanding survivin's structure and its interactions is vital for developing targeted therapeutics.
• Previous X-ray crystallography studies presented conflicting models for survivin's homodimerization interface.

Purpose of the Study:

• To elucidate the solution structure of the survivin homodimer using NMR spectroscopy.
• To identify the specific residues involved in survivin dimerization.
• To characterize the structural basis of survivin's interaction with Smac/Diablo.

Main Methods:

• Nuclear Magnetic Resonance (NMR) spectroscopy was employed to study survivin(1-120).
• Solution-state NMR experiments were performed to determine the protein's homodimer interface.
• NMR titration experiments were conducted to map the binding site of Smac/Diablo peptides.

Main Results:

• Survivin(1-120) forms a distinct bow-tie-shaped dimer in solution.
• The homodimer interface involves N-terminal residues and regions connecting the BIR domain to the C-terminal alpha helix.
• NMR data indicate that Smac/Diablo peptides bind to survivin across the third beta-strand, similar to its interaction with XIAP.
• Specific residues near alpha4 and beta3 of survivin are perturbed upon Smac/Diablo binding.

Conclusions:

• The solution structure of the survivin dimer resolves ambiguities from crystal structures.
• NMR provides a detailed understanding of survivin's homodimerization interface.
• The study reveals the structural mechanism underlying survivin's interaction with Smac/Diablo, offering insights for drug development.