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PDBsum entry 5v3p
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Hydrolase,ligase
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PDB id
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5v3p
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Contents |
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316 a.a.
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300 a.a.
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308 a.a.
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262 a.a.
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References listed in PDB file
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Key reference
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Title
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Denisovan, Modern human and mouse tnfaip3 alleles tune a20 phosphorylation and immunity.
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Authors
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N.W.Zammit,
O.M.Siggs,
P.E.Gray,
K.Horikawa,
D.B.Langley,
S.N.Walters,
S.R.Daley,
C.Loetsch,
J.Warren,
J.Y.Yap,
D.Cultrone,
A.Russell,
E.K.Malle,
J.E.Villanueva,
M.J.Cowley,
V.Gayevskiy,
M.E.Dinger,
R.Brink,
D.Zahra,
G.Chaudhri,
G.Karupiah,
B.Whittle,
C.Roots,
E.Bertram,
M.Yamada,
Y.Jeelall,
A.Enders,
B.E.Clifton,
P.D.Mabbitt,
C.J.Jackson,
S.R.Watson,
C.N.Jenne,
L.L.Lanier,
T.Wiltshire,
M.H.Spitzer,
G.P.Nolan,
F.Schmitz,
A.Aderem,
B.T.Porebski,
A.M.Buckle,
D.W.Abbott,
J.B.Ziegler,
M.E.Craig,
P.Benitez-Aguirre,
J.Teo,
S.G.Tangye,
C.King,
M.Wong,
M.P.Cox,
W.Phung,
J.Tang,
W.Sandoval,
I.E.Wertz,
D.Christ,
C.C.Goodnow,
S.T.Grey.
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Ref.
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Nat Immunol, 2019,
20,
1299-1310.
[DOI no: ]
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PubMed id
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Abstract
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Resisting and tolerating microbes are alternative strategies to survive
infection, but little is known about the evolutionary mechanisms controlling
this balance. Here genomic analyses of anatomically modern humans, extinct
Denisovan hominins and mice revealed a TNFAIP3 allelic series with alterations
in the encoded immune response inhibitor A20. Each TNFAIP3 allele encoded
substitutions at non-catalytic residues of the ubiquitin protease OTU domain
that diminished IκB kinase-dependent phosphorylation and activation of A20. Two
TNFAIP3 alleles encoding A20 proteins with partial phosphorylation deficits
seemed to be beneficial by increasing immunity without causing spontaneous
inflammatory disease: A20 T108A;I207L, originating in Denisovans and
introgressed in modern humans throughout Oceania, and A20 I325N, from an
N-ethyl-N-nitrosourea (ENU)-mutagenized mouse strain. By contrast, a rare human
TNFAIP3 allele encoding an A20 protein with 95% loss of phosphorylation, C243Y,
caused spontaneous inflammatory disease in humans and mice. Analysis of the
partial-phosphorylation A20 I325N allele in mice revealed diminished tolerance
of bacterial lipopolysaccharide and poxvirus inoculation as tradeoffs for
enhanced immunity.
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