A structured interdomain linker directs self-polymerization of human uromodulin

Area of Science:

• Biochemistry
• Structural Biology
• Nephrology

Background:

• Uromodulin (UMOD), the most abundant urinary protein, is vital for kidney health and a therapeutic target for hypertension.
• UMOD forms extracellular filaments via its ZP-N/ZP-C module, influencing electrolyte balance, immunity, and stone prevention.
• These filaments capture bacteria in urine, aiding clearance, but UMOD's self-assembly structure remained unknown.

Purpose of the Study:

• To determine the structural basis of Uromodulin (UMOD) filament formation.
• To elucidate the self-assembly mechanism of UMOD, a key urinary protein involved in kidney diseases.
• To compare the polymerization regions of UMOD with structurally related proteins like ZP2.

Main Methods:

• Crystal structure determination of polymerization regions of human UMOD.
• Structural analysis of mouse ZP2, a related protein forming heteropolymers.
• Comparative structural analysis of UMOD, ZP2, TECTA, and GP2.

Main Results:

• The crystal structure of UMOD reveals extensive hydrophobic interactions mediating ZP-N domain homodimerization.
• This homodimerization, facilitated by an ordered ZP-N/ZP-C linker unique to UMOD, is essential for filament formation.
• The UMOD structure contrasts with ZP2 and explains pathogenic mutations in UMOD and TECTA.

Conclusions:

• The UMOD structure provides the first insights into its filament self-assembly mechanism.
• Interdomain linker plasticity significantly influences the function of structurally similar multidomain proteins.
• Understanding UMOD's architecture rationalizes disease-associated mutations, paving the way for therapeutic strategies.