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Proc Natl Acad Sci U S A. 2016 Feb 9;113(6):1552-7. doi: 10.1073/pnas.1519803113. Epub 2016 Jan 25.

A structured interdomain linker directs self-polymerization of human uromodulin.

Author information

1
Department of Biosciences and Nutrition & Center for Innovative Medicine, Karolinska Institutet, SE-141 83 Huddinge, Sweden;
2
Molecular Genetics of Renal Disorders Unit, Division of Genetics and Cell Biology, San Raffaele Scientific Institute, I-20132 Milan, Italy;
3
European Synchrotron Radiation Facility - The European Synchrotron, Grenoble 38000, France.
4
Department of Biosciences and Nutrition & Center for Innovative Medicine, Karolinska Institutet, SE-141 83 Huddinge, Sweden; luca.jovine@ki.se.

Abstract

Uromodulin (UMOD)/Tamm-Horsfall protein, the most abundant human urinary protein, plays a key role in chronic kidney diseases and is a promising therapeutic target for hypertension. Via its bipartite zona pellucida module (ZP-N/ZP-C), UMOD forms extracellular filaments that regulate kidney electrolyte balance and innate immunity, as well as protect against renal stones. Moreover, salt-dependent aggregation of UMOD filaments in the urine generates a soluble molecular net that captures uropathogenic bacteria and facilitates their clearance. Despite the functional importance of its homopolymers, no structural information is available on UMOD and how it self-assembles into filaments. Here, we report the crystal structures of polymerization regions of human UMOD and mouse ZP2, an essential sperm receptor protein that is structurally related to UMOD but forms heteropolymers. The structure of UMOD reveals that an extensive hydrophobic interface mediates ZP-N domain homodimerization. This arrangement is required for filament formation and is directed by an ordered ZP-N/ZP-C linker that is not observed in ZP2 but is conserved in the sequence of deafness/Crohn's disease-associated homopolymeric glycoproteins α-tectorin (TECTA) and glycoprotein 2 (GP2). Our data provide an example of how interdomain linker plasticity can modulate the function of structurally similar multidomain proteins. Moreover, the architecture of UMOD rationalizes numerous pathogenic mutations in both UMOD and TECTA genes.

KEYWORDS:

X-ray crystallography; ZP2; polymerization; uromodulin; zona pellucida domain

PMID:
26811476
PMCID:
PMC4760807
DOI:
10.1073/pnas.1519803113
[Indexed for MEDLINE]
Free PMC Article

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