Protein Domain-Swapping Can Be a Consequence of Functional Residues

Area of Science:

• Protein folding and aggregation
• Biophysics
• Structural biology

Background:

• Monomer topology influences domain-swapping, a pathway to protein aggregation.
• Stefin-B, a protease inhibitor, domain swaps more readily than monellin (scMn), despite similar topology.
• Understanding the molecular basis for differential domain-swapping propensity is crucial.

Purpose of the Study:

• To computationally investigate the folding mechanisms of stefin-B and scMn.
• To elucidate the structural and functional reasons behind their differing domain-swapping tendencies.
• To correlate protein function constraints with folding intermediate formation and domain-swapping.

Main Methods:

• Structure-based computational simulations of protein folding.
• Analysis of folding pathways and intermediate states.
• Comparison of functional residue distribution in stefin-B and scMn.

Main Results:

• Monellin (scMn) folds cooperatively without intermediates, unlike stefin-B.
• Stefin-B populates a folding intermediate containing a single structured domain, facilitating domain-swapping.
• Localized protease-binding regions in stefin-B, but not distributed sweet-taste residues in monellin, cause this intermediate formation.

Conclusions:

• Localized functional regions in proteins can promote folding intermediates and subsequent domain-swapping.
• Distributed functional residues, as seen in monellin, may prevent intermediate formation and domain-swapping.
• Protein function imposes structural constraints that can directly lead to domain-swapping and potentially aggregation.