A structured interdomain linker directs self-polymerization of human uromodulin

Marcel Bokhove, Kaoru Nishimura, Martina Brunati, Ling Han, Daniele De Sanctis, Luca Rampoldi, Luca Jovine

Research output: Contribution to journalArticle

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, saltdependent 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.

Original languageEnglish
Pages (from-to)1552-1557
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume113
Issue number6
DOIs
Publication statusPublished - Feb 9 2016

Keywords

  • Polymerization
  • Uromodulin
  • X-ray crystallography
  • Zona pellucida domain
  • ZP2

ASJC Scopus subject areas

  • General

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