Cryo-EM structure of native human uromodulin, a zona pellucida module polymer
Alena Stsiapanava1, Chenrui Xu2,3, Martina Brunati4
1Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, Sweden.
The EMBO Journal
|November 16, 2020
Summary
The zona pellucida (ZP) domain forms essential extracellular filaments. This study reveals the detailed structure of uromodulin filaments, uncovering their role in bacterial defense and fertilization.
Area of Science:
- Biochemistry
- Structural Biology
- Molecular Biology
Background:
- Extracellular filaments and matrices are crucial for biological processes.
- The zona pellucida (ZP) domain is a conserved polymerization module involved in morphogenesis, hearing, fertilization, and defense.
- Detailed structural information on ZP domain-containing filamentous proteins is lacking.
Purpose of the Study:
- To determine the filamentous conformation of uromodulin (UMOD)/Tamm-Horsfall protein, an archetypal ZP module-containing molecule.
- To elucidate the structural basis for UMOD's function in biological processes.
Main Methods:
- Cryo-electron microscopy was used to study UMOD in its mature homopolymeric state.
- Structural analysis of the filamentous conformation and inter-subunit interactions.
Main Results:
- UMOD forms a one-start helix with a 180-degree twist between subunits.
- Interdomain linkers reorganize upon propeptide dissociation.
- Lateral interactions form sheets with binding sites for uropathogenic bacteria.
- Models suggest a common sperm-binding region in heteromeric egg coat filaments.
Conclusions:
- The study provides the first detailed structural insights into ZP module-containing filaments.
- UMOD filament structure explains its role in antibacterial defense and potentially fertilization.
- This work advances understanding of extracellular matrix assembly and function.
