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Title
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A structured interdomain linker directs self-polymerization of human uromodulin.
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Authors
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M.Bokhove,
K.Nishimura,
M.Brunati,
L.Han,
D.de Sanctis,
L.Rampoldi,
L.Jovine.
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Ref.
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Proc Natl Acad Sci U S A, 2016,
113,
1552-1557.
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PubMed id
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Abstract
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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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