Cryo-EM structure of native human uromodulin, a zona pellucida module polymer.

The EMBO Journal
A. StsiapanavaLuca Jovine

Abstract

Assembly of extracellular filaments and matrices mediating fundamental biological processes such as morphogenesis, hearing, fertilization, and antibacterial defense is driven by a ubiquitous polymerization module known as zona pellucida (ZP) "domain". Despite the conservation of this element from hydra to humans, no detailed information is available on the filamentous conformation of any ZP module protein. Here, we report a cryo-electron microscopy study of uromodulin (UMOD)/Tamm-Horsfall protein, the most abundant protein in human urine and an archetypal ZP module-containing molecule, in its mature homopolymeric state. UMOD forms a one-start helix with an unprecedented 180-degree twist between subunits enfolded by interdomain linkers that have completely reorganized as a result of propeptide dissociation. Lateral interaction between filaments in the urine generates sheets exposing a checkerboard of binding sites to capture uropathogenic bacteria, and UMOD-based models of heteromeric vertebrate egg coat filaments identify a common sperm-binding region at the interface between subunits.

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Citations

Nov 17, 2020·The EMBO Journal·Alena StsiapanavaLuca Jovine
Feb 5, 2021·Frontiers in Cell and Developmental Biology·Mª José Izquierdo-RicoManuel Avilés
Feb 11, 2021·Annual Review of Physiology·Céline SchaefferLuca Rampoldi
Feb 8, 2021·Kidney International·Andrew Beenken, Qais Al-Awqati

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Methods Mentioned

BETA
glycosylation
light scattering
PISA

Software Mentioned

HHpred
CTFFIND
EPU
Illustrate
Cryo
RELION
CCP
EMAN2
MotionCor2
PISA

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