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0:00
Hello. My name is Kayoko Tanaka.
I'm a lecturer at the
University of Leicester.
I'd like to introduce
the research topic of
the KRAS Pathway and
Mutations in Cancer.
0:15
My presentation consists of
six parts as listed here.
In the first three
parts, I will summarize
the structural and biochemical
properties of KRAS
and their relevance to
oncogenic mutations.
Next, I would like to introduce
the importance of
distinguishing between
the effects of overexpression
and endogenous expression
of oncogenic KRAS mutants
as these lead to
different phenotypes.
Following that, I will discuss
the downstream pathways of KRAS.
I will highlight
the significance of
the Raf-MEK-ERK signaling axis
in KRAS oncogenic signaling.
Finally, I would like to discuss
the molecular insights into
the KRAS-Rgl2-RalA/B
signaling axis.
1:11
First, KRAS is an isoform
of the Ras family
of small GTPases.
1:19
Humans have three Ras genes,
KRAS, HRAS, and NRAS.
As the KRAS encodes
two splice variants,
KRAS4A and KRAS4B,
there are four Ras
isoforms as listed here.
The diagram represents an
NMR data-driven model of
KRAS4B PDB entry 2MSD
and is colored in the same way
as the sequence alignment.
These four isoforms are
highly conserved at
the N-terminal hub
which consists of
β1, α1, β2, β3, α2, and β4
and the linking
unstructured parts P-loop,
Switch I, Switch II.
They further contribute
to generating
a guanine nucleotide
binding pocket.
Meanwhile, the C-terminal
end is less conserved
and hence is as termed
the hypervariable region,
which contains cysteine
residues that receive
lipid modifications
that help the proteins
to anchor at the
plasma membrane.
This is the same NMR
data-driven model
of KRAS4B that I just presented,
but this time it includes
the membrane nanodisc as
the original modeled KRAS
structure was analyzed.
Mazhab-Jafari and his
colleagues performed
a paramagnetic relaxation
enhancement analysis,
type of NMR analysis,
to examine the molecular
orientation of KRAS
in relation to the
membrane nanodisc.
The C-terminal hypervariable
region is highlighted in purple
and the guanine nucleotide
is indicated in the model.
Additionally, the
modeled structure shows
the position of the magnesium
ion, which is essential
for the proper folding
of the KRAS protein.
This study emphasizes
the importance
of considering the
effects of the membrane
when investigating KRAS function
as the presence of the membrane
can impose constraints
on KRAS orientation
and the accessibility of
its interacting partners.
