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- W2263502853 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." @default.
- W2263502853 created "2016-06-24" @default.
- W2263502853 creator A5000168860 @default.
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- W2263502853 creator A5070531756 @default.
- W2263502853 creator A5085610458 @default.
- W2263502853 creator A5088469727 @default.
- W2263502853 date "2016-01-25" @default.
- W2263502853 modified "2023-10-04" @default.
- W2263502853 title "A structured interdomain linker directs self-polymerization of human uromodulin" @default.
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- W2263502853 doi "https://doi.org/10.1073/pnas.1519803113" @default.
- W2263502853 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/4760807" @default.
- W2263502853 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/26811476" @default.
- W2263502853 hasPublicationYear "2016" @default.
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