Evolution of fold switching in a metamorphic protein

Area of Science:

• Biochemistry
• Evolutionary Biology
• Structural Biology

Background:

• Metamorphic proteins challenge the traditional protein folding paradigm by adopting multiple distinct structures.
• The evolutionary mechanisms driving the emergence of protein metamorphosis remain largely unknown.
• The chemokine family typically features proteins with a single conserved fold, making human protein XCL1 an outlier.

Purpose of the Study:

• To investigate the evolutionary trajectory of the metamorphic human protein XCL1.
• To understand the molecular basis for the evolution of fold switching in XCL1.
• To elucidate the principles governing how a single protein sequence can encode multiple functional structures.

Main Methods:

• Ancestral sequence reconstruction to infer ancestral protein states.
• Nuclear magnetic resonance (NMR) spectroscopy to determine protein structures.
• Analysis of structural constraints, dimer interfaces, and intramolecular contacts.

Main Results:

• Human protein XCL1 evolved from an ancestor possessing the canonical chemokine fold.
• Key evolutionary events included the development of a dimer interface, altered structural constraints, and modified intramolecular contacts.
• XCL1's evolution likely involved a period of preferential population of its noncanonical fold before achieving its current dual-fold state.

Conclusions:

• The evolution of metamorphosis in XCL1 was driven by specific changes in its sequence and structural interactions.
• These findings provide insights into the evolutionary pathways leading to proteins with multiple structures.
• The study reveals fundamental principles applicable to protein design and engineering for novel functions.