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PDBsum entry 1vyh
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Contents |
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(+ 4 more)
218 a.a.
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(+ 4 more)
310 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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Coupling paf signaling to dynein regulation: structure of lis1 in complex with paf-Acetylhydrolase.
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Authors
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C.Tarricone,
F.Perrina,
S.Monzani,
L.Massimiliano,
M.H.Kim,
Z.S.Derewenda,
S.Knapp,
L.H.Tsai,
A.Musacchio.
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Ref.
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Neuron, 2004,
44,
809-821.
[DOI no: ]
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PubMed id
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Abstract
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Mutations in the LIS1 gene cause lissencephaly, a human neuronal migration
disorder. LIS1 binds dynein and the dynein-associated proteins Nde1 (formerly
known as NudE), Ndel1 (formerly known as NUDEL), and CLIP-170, as well as the
catalytic alpha dimers of brain cytosolic platelet activating factor
acetylhydrolase (PAF-AH). The mechanism coupling the two diverse regulatory
pathways remains unknown. We report the structure of LIS1 in complex with the
alpha2/alpha2 PAF-AH homodimer. One LIS1 homodimer binds symmetrically to one
alpha2/alpha2 homodimer via the highly conserved top faces of the LIS1 beta
propellers. The same surface of LIS1 contains sites of mutations causing
lissencephaly and overlaps with a putative dynein binding surface. Ndel1
competes with the alpha2/alpha2 homodimer for LIS1, but the interaction is
complex and requires both the N- and C-terminal domains of LIS1. Our data
suggest that the LIS1 molecule undergoes major conformational rearrangement when
switching from a complex with the acetylhydrolase to the one with Ndel1.
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Figure 3.
Figure 3. Comparison of LIS1/PAF-AH and G[αβγ](A) Ribbon
diagram of the G[αβγ] trimer based on PDB coordinates 1GP2
(Wall et al., 1995). G[α] is yellow and is subdivided in the
Ras-like domain (light yellow) and in the helical domain (dark
yellow). G[β] is cyan and G[γ] is green. The G[α]-G[βγ]
interaction involves the N-terminal helix and the switch I and
switch II regions of G[α] (red). The G[β] subunit uses the top
surface of the β propeller, where the outer βD strand connects
to the inner βA strand of the next blade to bind G[α]. The
top surface is preferentially used for ligand recognition by
propeller-like structures (Smith et al., 1999).(B) A LIS1/PAF-AH
hemitetramer is shown. The α[2] subunit has the same
orientation of the G[α] subunit shown in (A). The orientation
of the β subunits is unrelated, although also in this case the
top surface of the propeller is used for binding.
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Figure 7.
Figure 7. A Model for LIS1/Ndel1 and Its Interacton with
DyneinTo reconcile the two-fold symmetry of LIS1 with that of
Ndel1, we postulated that Ndel1 forms an antiparallel coiled
coil. The α4 helices of N-LIS1 interact with Ndel1, and so does
the β propeller region. The two β propellers of LIS1 bind
dynein at distinct sites in the first AAA module and in the stem
(Tai et al., 2002). Because the dynein heavy chain that
contributes a sizable fraction of the stem is a dimer (Holzbaur
and Vallee, 1994), the overall assembly may be duplicated
(represented by the gray, dashed drawing).
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The above figures are
reprinted
by permission from Cell Press:
Neuron
(2004,
44,
809-821)
copyright 2004.
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