Abstract
The glycoprotein uromodulin (UMOD) is the most abundant protein in human urine and forms filamentous homopolymers that encapsulate and aggregate uropathogens, promoting pathogen clearance by urine excretion. Despite its critical role in the innate immune response against urinary tract infections, the structural basis and mechanism of UMOD polymerization remained unknown. Here, we present the cryo-EM structure of the UMOD filament core at 3.5 Å resolution, comprised of the bipartite zona pellucida (ZP) module in a helical arrangement with a rise of ~65 Å and a twist of ~180°. The immunoglobulin-like ZPN and ZPC subdomains of each monomer are separated by a long linker that interacts with the preceding ZPC and following ZPN subdomains by β-sheet complementation. The unique filament architecture suggests an assembly mechanism in which subunit incorporation could be synchronized with proteolytic cleavage of the C-terminal pro-peptide that anchors assembly-incompetent UMOD precursors to the membrane.
Highlights
The glycoprotein uromodulin (UMOD) is the most abundant protein in human urine and forms filamentous homopolymers that encapsulate and aggregate uropathogens, promoting pathogen clearance by urine excretion
ZPC subdomains of each monomer are separated by a long linker that interacts with the preceding ZPC and following ZPN subdomains by β-sheet complementation
The unique filament architecture suggests an assembly mechanism in which subunit incorporation could be synchronized with proteolytic cleavage of the C-terminal pro-peptide that anchors assembly-incompetent UMOD precursors to the membrane
Summary
A structured interdomain linker directs self-polymerization of human uromodulin. Brunati M, Perucca S, Han L, Cattaneo A, Consolato F, Andolfo A, Schaeffer C, Olinger E, Peng J, Santambrogio S, Perrier R, Li S, Bokhove M, Bachi A, Hummler E, Devuyst O, Wu. Q, Jovine L, Rampoldi L. NJ, Scharf J, Schunkert H, Shoemaker MB, Sklar P, Soininen H, Sokol H, Spector T, Sullivan PF, Suvisaari J, Tai ES, Teo YY, Tiinamaija T, Tsuang M, Turner D, Tusie-Luna T, Vartiainen E, Ware JS, Watkins H, Weersma RK, Wessman M, Wilson JG, Xavier RJ, Neale BM, Daly MJ, MacArthur DG. Uromodulin (Tamm-Horsfall glycoprotein/uromucoid) is a phosphatidylionositol-linked membrane protein. Analysis of uromodulin polymerization provides new insights into the mechanisms regulating ZP domainmediated protein assembly. New tools for automated high-resolution cryo-EM structure determination in RELION-3
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