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References listed in PDB file
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Key reference
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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.
[DOI no: ]
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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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Secondary reference #1
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Title
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Characterization and separation of an inhibitor of viral hemagglutination present in urine.
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Authors
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I.Tamm,
F.L.Horsfall.
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Ref.
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Proc Soc Exp Biol Med, 1950,
74,
106-108.
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PubMed id
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Secondary reference #2
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Title
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Isolation of the cdna encoding glycoprotein-2 (gp-2), The major zymogen granule membrane protein. Homology to uromodulin/tamm-Horsfall protein.
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Authors
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T.C.Hoops,
M.J.Rindler.
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Ref.
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J Biol Chem, 1991,
266,
4257-4263.
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PubMed id
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Secondary reference #3
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Title
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Mutations in the human alpha-Tectorin gene cause autosomal dominant non-Syndromic hearing impairment.
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Authors
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K.Verhoeven,
L.Van laer,
K.Kirschhofer,
P.K.Legan,
D.C.Hughes,
I.Schatteman,
M.Verstreken,
P.Van hauwe,
P.Coucke,
A.Chen,
R.J.Smith,
T.Somers,
F.E.Offeciers,
P.Van de heyning,
G.P.Richardson,
F.Wachtler,
W.J.Kimberling,
P.J.Willems,
P.J.Govaerts,
G.Van camp.
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Ref.
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Nat Genet, 1998,
19,
60-62.
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PubMed id
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Secondary reference #4
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Title
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The zp domain is a conserved module for polymerization of extracellular proteins.
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Authors
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L.Jovine,
H.Qi,
Z.Williams,
E.Litscher,
P.M.Wassarman.
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Ref.
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Nat Cell Biol, 2002,
4,
457-461.
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PubMed id
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Secondary reference #5
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Title
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Tamm-Horsfall glycoprotein: biology and clinical relevance.
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Authors
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F.Serafini-Cessi,
N.Malagolini,
D.Cavallone.
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Ref.
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Am J Kidney Dis, 2003,
42,
658-676.
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PubMed id
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Secondary reference #6
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Title
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A duplicated motif controls assembly of zona pellucida domain proteins.
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Authors
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L.Jovine,
H.Qi,
Z.Williams,
E.S.Litscher,
P.M.Wassarman.
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Ref.
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Proc Natl Acad Sci U S A, 2004,
101,
5922-5927.
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PubMed id
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Secondary reference #7
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Title
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Zona pellucida domain proteins.
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Authors
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L.Jovine,
C.C.Darie,
E.S.Litscher,
P.M.Wassarman.
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Ref.
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Annu Rev Biochem, 2005,
74,
83.
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PubMed id
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Secondary reference #8
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Title
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Insights into egg coat assembly and egg-Sperm interaction from the X-Ray structure of full-Length zp3.
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Authors
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L.Han,
M.Monné,
H.Okumura,
T.Schwend,
A.L.Cherry,
D.Flot,
T.Matsuda,
L.Jovine.
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Ref.
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Cell, 2010,
143,
404-415.
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PubMed id
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Secondary reference #9
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Title
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The rediscovery of uromodulin (tamm-Horsfall protein): from tubulointerstitial nephropathy to chronic kidney disease.
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Authors
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L.Rampoldi,
F.Scolari,
A.Amoroso,
G.Ghiggeri,
O.Devuyst.
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Ref.
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Kidney Int, 2011,
80,
338-347.
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PubMed id
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