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PDBsum entry 5bxl
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Contents |
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250 a.a.
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244 a.a.
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240 a.a.
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235 a.a.
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231 a.a.
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243 a.a.
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241 a.a.
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222 a.a.
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204 a.a.
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195 a.a.
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212 a.a.
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222 a.a.
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229 a.a.
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196 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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Defective immuno- And thymoproteasome assembly causes severe immunodeficiency.
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Authors
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I.Treise,
E.M.Huber,
T.Klein-Rodewald,
W.Heinemeyer,
S.A.Grassmann,
M.Basler,
T.Adler,
B.Rathkolb,
L.Helming,
C.Andres,
M.Klaften,
C.Landbrecht,
T.Wieland,
T.M.Strom,
K.D.Mccoy,
A.J.Macpherson,
E.Wolf,
M.Groettrup,
M.Ollert,
F.Neff,
V.Gailus-Durner,
H.Fuchs,
M.Hrabě de angelis,
M.Groll,
D.H.Busch.
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Ref.
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Sci Rep, 2018,
8,
5975.
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PubMed id
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Abstract
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By N-ethyl-N-nitrosourea (ENU) mutagenesis, we generated the mutant mouse line
TUB6 that is characterised by severe combined immunodeficiency (SCID) and
systemic sterile autoinflammation in homozygotes, and a selective T cell defect
in heterozygotes. The causative missense point mutation results in the single
amino acid exchange G170W in multicatalytic endopeptidase complex subunit-1
(MECL-1), the β2i-subunit of the immuno- and thymoproteasome. Yeast mutagenesis
and crystallographic data suggest that the severe TUB6-phenotype compared to the
MECL-1 knockout mouse is caused by structural changes in the C-terminal
appendage of β2i that prevent the biogenesis of immuno- and thymoproteasomes.
Proteasomes are essential for cell survival, and defective proteasome assembly
causes selective death of cells expressing the mutant MECL-1, leading to the
severe immunological phenotype. In contrast to the immunosubunits β1i (LMP2)
and β5i (LMP7), mutations in the gene encoding MECL-1 have not yet been
assigned to human disorders. The TUB6 mutant mouse line exemplifies the
involvement of MECL-1 in immunopathogenesis and provides the first mouse model
for primary immuno- and thymoproteasome-associated immunodeficiency that may
also be relevant in humans.
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