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PDBsum entry 3bs7
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Signaling protein
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PDB id
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3bs7
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Contents |
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* Residue conservation analysis
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DOI no:
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Proc Natl Acad Sci U S A
105:2836-2841
(2008)
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PubMed id:
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CNK and HYP form a discrete dimer by their SAM domains to mediate RAF kinase signaling.
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T.Rajakulendran,
M.Sahmi,
I.Kurinov,
M.Tyers,
M.Therrien,
F.Sicheri.
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ABSTRACT
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RAF kinase functions in the mitogen-activated protein kinase (MAPK) pathway to
transmit growth signals to the downstream kinases MEK and ERK. Activation of RAF
catalytic activity is facilitated by a regulatory complex comprising the
proteins CNK (Connector enhancer of KSR), HYP (Hyphen), and KSR (Kinase
Suppressor of Ras). The sterile alpha-motif (SAM) domain found in both CNK and
HYP plays an essential role in complex formation. Here, we have determined the
x-ray crystal structure of the SAM domain of CNK in complex with the SAM domain
of HYP. The structure reveals a single-junction SAM domain dimer of 1:1
stoichiometry in which the binding mode is a variation of polymeric SAM domain
interactions. Through in vitro and in vivo mutational analyses, we show that the
specific mode of dimerization revealed by the crystal structure is essential for
RAF signaling and facilitates the recruitment of KSR to form the CNK/HYP/KSR
regulatory complex. We present two docking-site models to account for how SAM
domain dimerization might influence the formation of a higher-order CNK/HYP/KSR
complex.
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Selected figure(s)
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Figure 1.
The SAM domains of CNK and HYP interact directly. (A) Domain
architecture of CNK and HYP. CNK is characterized by the
presence of a SAM (sterile α-motif) domain; a CRIC (conserved
region in CNK); a PDZ (PSD-95, ZO-1/2, Dlg-1) domain; and a PH
(pleckstrin homology) domain. HYP contains a single SAM domain.
Indicated protein sizes correspond to the Drosophila members.
(B) Pull-down analysis of GST-dHYP^SAM with hCNK2^SAM. GST and
GST-Vts1^SAM served as controls.
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Figure 3.
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Figures were
selected
by an automated process.
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Literature references that cite this PDB file's key reference
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PubMed id
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Reference
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C.M.Udell,
T.Rajakulendran,
F.Sicheri,
and
M.Therrien
(2011).
Mechanistic principles of RAF kinase signaling.
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Cell Mol Life Sci,
68,
553-565.
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J.Ding,
O.Tchaicheeyan,
and
L.Ambrosio
(2010).
Drosophila Raf's N terminus contains a novel conserved region and can contribute to torso RTK signaling.
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Genetics,
184,
717-729.
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J.Lim,
M.Zhou,
T.D.Veenstra,
and
D.K.Morrison
(2010).
The CNK1 scaffold binds cytohesins and promotes insulin pathway signaling.
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Genes Dev,
24,
1496-1506.
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R.L.Rich,
and
D.G.Myszka
(2010).
Grading the commercial optical biosensor literature-Class of 2008: 'The Mighty Binders'.
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J Mol Recognit,
23,
1.
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M.Leone,
J.Cellitti,
and
M.Pellecchia
(2009).
The Sam domain of the lipid phosphatase Ship2 adopts a common model to interact with Arap3-Sam and EphA2-Sam.
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BMC Struct Biol,
9,
59.
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PDB code:
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M.Leone,
J.Cellitti,
and
M.Pellecchia
(2008).
NMR studies of a heterotypic Sam-Sam domain association: the interaction between the lipid phosphatase Ship2 and the EphA2 receptor.
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Biochemistry,
47,
12721-12728.
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PDB code:
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The most recent references are shown first.
Citation data come partly from CiteXplore and partly
from an automated harvesting procedure. Note that this is likely to be
only a partial list as not all journals are covered by
either method. However, we are continually building up the citation data
so more and more references will be included with time.
Where a reference describes a PDB structure, the PDB
code is
shown on the right.
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Links
