Specific binding-induced modulation of the XCL1 metamorphic equilibrium.

Area of Science:

• * Molecular biology
• * Immunology
• * Protein engineering

Background:

• * The chemokine XCL1 is a metamorphic protein, existing in two distinct native structures with different functions in the human immune system.
• * One structure binds receptors for immune signaling, while the other has antimicrobial activity and binds glycosaminoglycans.
• * Spontaneous and reversible structural switching occurs under physiological conditions, complicating functional studies.

Purpose of the Study:

• * To develop a molecular tool to regulate XCL1's structural interconversion.
• * To investigate methods for controlling the balance between XCL1's receptor-binding and antimicrobial structures.
• * To lay the groundwork for understanding XCL1's role in health and disease.

Main Methods:

• * Heparin affinity chromatography.
• * Nuclear Magnetic Resonance (NMR) spectroscopy.
• * Engineering of an XCL1 variant (CC5).

Main Results:

• * The engineered XCL1 variant, CC5, induces a dose-dependent shift in XCL1's metamorphic equilibrium.
• * CC5 favors the dimeric, all-β antimicrobial structure over the α-β receptor-binding structure.
• * This shift is attributed to the formation of XCL1-CC5 heterodimers adopting the β-sheet conformation.

Conclusions:

• * Protein metamorphosis is druggable, offering new therapeutic strategies.
• * The engineered CC5 variant provides a tool to study XCL1's functional roles.
• * This work opens avenues for controlling metamorphic protein functions by modulating their structural populations.