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Structural Biology 2018
Volume: 4
Biochemistry & Molecular Biology Journal
Page 67
March 15-16 2018
Barcelona, Spain
10
th
Edition of International Conference on
Structural Biology
T
he dynein motor protein family, consisting of cytoplasmic and
axonemal isoforms, generates movement along microtubules
in the minus end direction in eukaryotic cells. Cytoplasmic
dynein-1 (dynein-1) carries out most microtubule minus end
directed transport and its cargoes include mitochondria, nuclei,
as well as protein and mRNA complexes. It also plays important
roles duringmitosis, where dynein-1participates in the breakdown
of the nuclear envelope and the control of the spindle assembly
checkpoint. Cytoplasmic dynein-2 (dynein-2) is involved in the
intraflagellar transport in cilia and axonemal dyneins drive the
beating movement of the motile cilia subpopulation. Mutations in
dynein motors are associated with neurodegenerative diseases,
skeletal ciliopathies and primary ciliary dyskinesia. All dyneins
exist asmulti protein complexeswithmolecular weights of around
1.4 MDa. They contain a 3500 amino-acid residue motor domain
consisting of a ring of six AAA+ domains (ATPases associated
with diverse cellular activities), the linker and an elongated coiled-
coil helix with the microtubule binding domain (MTBD) at its tip.
ATP hydrolysis causes the linker to switch between a post and
pre-powerstroke conformation to produce the necessary force
for movement. The linker swing is also synchronized with cycles
of microtubule binding/release in the MTBD; another important
prerequisite for efficient movement. Previously, it was unknown
how ATP hydrolysis causes linker remodeling and how this
remodeling is correlated with microtubule binding/release. We
intend to present two dynein motor crystal structures: dynein-1
from
Saccharomyces cerevisiae
in the apo state and dynein-2
from
Homo sapiens
in complex with the ATP hydrolysis transition
state analogue ADP.vanadate. These two structures reveal
that ATP hydrolysis causes the AAA+ ring to change from an
open to a closed conformation. The closure of the AAA+ ring
leads to a steric clash with the linker N-terminal domain, which
is subsequently forced to switch from the post- to the pre-
powerstroke conformation by a rigid-body movement. AAA+ ring
closure also induces a sliding movement within the coiled-coil
helix that causes the MTBD to release from the microtubule. The
open-to-closed transition of the AAA+ ring is therefore crucial for
the coordination of linker swing and the regulation of microtubule
binding.
schmidth@igbmc.frStructural insights into the dynein motor domain mechanism
Helgo Schmidt, Emma S Gleave
and
Andrew P Carter
Institut de Génétique et Biologie Moléculaire et Cellulaire, France
Biochem Mol biol J, Volume 4
DOI: 10.21767/2471-8084-C1-009