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PDBsum entry 3gmh
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References listed in PDB file
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Key reference
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Title
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Structure of an intermediate conformer of the spindle checkpoint protein mad2.
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Authors
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M.Hara,
E.Özkan,
H.Sun,
H.Yu,
X.Luo.
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Ref.
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Proc Natl Acad Sci U S A, 2015,
112,
11252-11257.
[DOI no: ]
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PubMed id
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Abstract
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The spindle checkpoint senses unattached kinetochores during prometaphase and
inhibits the anaphase-promoting complex or cyclosome (APC/C), thus ensuring
accurate chromosome segregation. The checkpoint protein mitotic arrest deficient
2 (Mad2) is an unusual protein with multiple folded states. Mad2 adopts the
closed conformation (C-Mad2) in a Mad1-Mad2 core complex. In mitosis,
kinetochore-bound Mad1-C-Mad2 recruits latent, open Mad2 (O-Mad2) from the
cytosol and converts it to an intermediate conformer (I-Mad2), which can then
bind and inhibit the APC/C activator cell division cycle 20 (Cdc20) as C-Mad2.
Here, we report the crystal structure and NMR analysis of I-Mad2 bound to
C-Mad2. Although I-Mad2 retains the O-Mad2 fold in crystal and in solution, its
core structural elements undergo discernible rigid-body movements and more
closely resemble C-Mad2. Residues exhibiting methyl chemical shift changes in
I-Mad2 form a contiguous, interior network that connects its C-Mad2-binding site
to the conformationally malleable C-terminal region. Mutations of residues at
the I-Mad2-C-Mad2 interface hinder I-Mad2 formation and impede the structural
transition of Mad2. Our study provides insight into the conformational
activation of Mad2 and establishes the basis of allosteric communication between
two distal sites in Mad2.
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