ArticleProceedings of the National Academy of Sciences of the United States of America2016
A structured interdomain linker directs self-polymerization of human uromodulin.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 59 papers.
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59 citing papers in PubMed, 103 citations in OpenAlex.
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- The role of uromodulin in cardiovascular disease: a review.Frontiers in cardiovascular medicine · 2024Review
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- Tamm-Horsfall protein in humane urine: sex-dependent differences in the excretion and N-glycosylation pattern.Scientific reports · 2023Article
- Unveiling the Hidden Power of Uromodulin: A Promising Potential Biomarker for Kidney Diseases.Diagnostics (Basel, Switzerland) · 2023Review
- Deciphering the Kidney Matrisome: Identification and Quantification of Renal Extracellular Matrix Proteins in Healthy Mice.International journal of molecular sciences · 2023Article
- Zona Pellucida like Domain Protein 1 (ZPLD1) Polymerization Is Regulated by Two Distinguished Hydrophobic Motifs.International journal of molecular sciences · 2022Article
- Evolving Concepts in Uromodulin Biology, Physiology, and Its Role in Disease: a Tale of Two Forms.Hypertension (Dallas, Tex. : 1979) · 2022Review
- Role of Uromodulin in Salt-Sensitive Hypertension.Hypertension (Dallas, Tex. : 1979) · 2022Review
- Uromodulin Regulates Murine Aquaporin-2 Activity via Thick Ascending Limb-Collecting Duct Cross-Talk during Water Deprivation.International journal of molecular sciences · 2022Article
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7 authors at 2 institutions in 2 countries.
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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.
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