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The cryo-EM structure of the human uromodulin filament core reveals a unique assembly mechanism.

<div class='caption-title'>Cryo-EM structure of the human UMOD filament core.</div>
<div class='caption-title'>Cryo-EM data evaluation for UMOD filaments.</div>
<div class='caption-title'>Representative image of the high-resolution cryoSPARC Coulomb potential map fitted with the asymmetric unit (AU) UMOD model.</div>
Stanisich JJ, Zyla DS, Afanasyev P, Xu J, Kipp A, Olinger E, Devuyst O, Pilhofer M, Boehringer D, Glockshuber R
OpenAccess logo Elife 9 (2020)
Cited: 12 times
EuropePMC logo PMID: 32815518

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.

Reviews citing this publication (5)

  1. Better, Faster, Cheaper: Recent Advances in Cryo-Electron Microscopy. Chua EYD, Mendez JH, Rapp M, Ilca SL, Tan YZ, Maruthi K, Kuang H, Zimanyi CM, Cheng A, Eng ET, Noble AJ, Potter CS, Carragher B. Annu Rev Biochem 91 1-32 (2022)
  2. Cryo-electron microscopy of cholinesterases, present and future. Leung MR, Zeev-Ben-Mordehai T. J Neurochem 158 1236-1243 (2021)
  3. Mechanistic interactions of uromodulin with the thick ascending limb: perspectives in physiology and hypertension. Boder P, Mary S, Mark PB, Leiper J, Dominiczak AF, Padmanabhan S, Rampoldi L, Delles C. J Hypertens 39 1490-1504 (2021)
  4. UMOD and the architecture of kidney disease. Devuyst O, Bochud M, Olinger E. Pflugers Arch 474 771-781 (2022)
  5. Evolving Concepts in Uromodulin Biology, Physiology, and Its Role in Disease: a Tale of Two Forms. LaFavers KA, Micanovic R, Sabo AR, Maghak LA, El-Achkar TM. Hypertension 79 2409-2418 (2022)

Articles citing this publication (7)

  1. Cryo-EM structure of native human uromodulin, a zona pellucida module polymer. Stsiapanava A, Xu C, Brunati M, Zamora-Caballero S, Schaeffer C, Bokhove M, Han L, Hebert H, Carroni M, Yasumasu S, Rampoldi L, Wu B, Jovine L. EMBO J 39 e106807 (2020)
  2. A C. elegans Zona Pellucida domain protein functions via its ZPc domain. Cohen JD, Bermudez JG, Good MC, Sundaram MV. PLoS Genet 16 e1009188 (2020)
  3. Donor-strand exchange drives assembly of the TasA scaffold in Bacillus subtilis biofilms. Böhning J, Ghrayeb M, Pedebos C, Abbas DK, Khalid S, Chai L, Bharat TAM. Nat Commun 13 7082 (2022)
  4. Meta-GWAS Reveals Novel Genetic Variants Associated with Urinary Excretion of Uromodulin. Joseph CB, Mariniello M, Yoshifuji A, Schiano G, Lake J, Marten J, Richmond A, Huffman JE, Campbell A, Harris SE, Troyanov S, Cocca M, Robino A, Thériault S, Eckardt KU, Wuttke M, Cheng Y, Corre T, Kolcic I, Black C, Bruat V, Concas MP, Sala C, Aeschbacher S, Schaefer F, Bergmann S, Campbell H, Olden M, Polasek O, Porteous DJ, Deary IJ, Madore F, Awadalla P, Girotto G, Ulivi S, Conen D, Wuehl E, Olinger E, Wilson JF, Bochud M, Köttgen A, Hayward C, Devuyst O. J Am Soc Nephrol 33 511-529 (2022)
  5. Structure of the decoy module of human glycoprotein 2 and uromodulin and its interaction with bacterial adhesin FimH. Stsiapanava A, Xu C, Nishio S, Han L, Yamakawa N, Carroni M, Tunyasuvunakool K, Jumper J, de Sanctis D, Wu B, Jovine L. Nat Struct Mol Biol 29 190-193 (2022)
  6. The kidney releases a nonpolymerizing form of uromodulin in the urine and circulation that retains the external hydrophobic patch domain. Micanovic R, LaFavers KA, Patidar KR, Ghabril MS, Doud EH, Mosley AL, Sabo AR, Khan S, El-Achkar TM. Am J Physiol Renal Physiol 322 F403-F418 (2022)
  7. Zona Pellucida like Domain Protein 1 (ZPLD1) Polymerization Is Regulated by Two Distinguished Hydrophobic Motifs. Knepper MI, Dernedde J. Int J Mol Sci 23 13894 (2022)


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