Hierarchical folding-upon-binding of an intrinsically disordered protein

Area of Science:

• Biochemistry
• Structural Biology
• Molecular Biology

Background:

• Intrinsically disordered proteins (IDPs) often bind partners via short linear motifs.
• Some IDPs utilize extended regions with multiple recognition elements for binding, but their folding mechanisms are unclear.

Purpose of the Study:

• To elucidate the folding-upon-binding mechanism of IDPs that use extended regions.
• To characterize the folding intermediates and conformational transitions involved.

Main Methods:

• Nuclear Magnetic Resonance (NMR) spectroscopy
• X-ray crystallography

Main Results:

• Resolved the atomic-resolution structure of POSH protein transitioning to a Rac1-bound state.
• Identified two distinct, structurally defined folding intermediates during POSH-Rac1 binding.
• Demonstrated a hierarchical folding process where each element's folding depends on the prior one.

Conclusions:

• IDPs can exhibit hierarchical folding-upon-binding mechanisms involving extended regions.
• Targeting folding intermediates and conformational transitions offers therapeutic potential for IDPs.