 |
PDBsum entry 2eyx
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Signaling protein
|
PDB id
|
|
|
|
2eyx
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
References listed in PDB file
|
|
|
Key reference
|
|
|
Title
|
|
Structural basis for the transforming activity of human cancer-Related signaling adaptor protein crk.
|
|
|
Authors
|
|
Y.Kobashigawa,
M.Sakai,
M.Naito,
M.Yokochi,
H.Kumeta,
Y.Makino,
K.Ogura,
S.Tanaka,
F.Inagaki.
|
|
|
Ref.
|
|
Nat Struct Mol Biol, 2007,
14,
503-510.
[DOI no: ]
|
|
|
PubMed id
|
|
|
|
|
|
Abstract
|
|
|
CRKI (SH2-SH3) and CRKII (SH2-SH3-SH3) are splicing isoforms of the oncoprotein
CRK that regulate transcription and cytoskeletal reorganization for cell growth
and motility by linking tyrosine kinases to small G proteins. CRKI shows
substantial transforming activity, whereas the activity of CRKII is low, and
phosphorylated CRKII has no biological activity whatsoever. The molecular
mechanisms underlying the distinct biological activities of the CRK proteins
remain elusive. We determined the solution structures of CRKI, CRKII and
phosphorylated CRKII by NMR and identified the molecular mechanism that gives
rise to their activities. Results from mutational analysis using rodent 3Y1
fibroblasts were consistent with those from the structural studies. Together,
these data suggest that the linker region modulates the binding of CRKII to its
targets, thus regulating cell growth and motility.
|
|
|
|
|
|
|
|
Figure 1.
Figure 1. NMR structures of CRKI, CRKII and pCRKII[1–228].
(a) Domain structures. Tyr221 is the cABL phosphorylation site.
(b–d) Superpositions of 20 lowest-energy structures of CRKI
SH2 (b, left), CRKI SH3 (b, right), CRKII (c), pCRKII[1–228]
SH2 (d, left) and pCRKII[1–228] nSH3 (d, right). Magenta, SH2
(residues 10–120); green, nSH3 (134–191); blue, cSH3
(238–293); yellow, ISC (220–237) (e) Ribbon representation
of CRKII (left) and pCRKII[1–228] (right), colored as in
b–d. In both structures, nSH3 is presented in the same
orientation; ligand-binding sites in SH2 and SH3 are circled
(dotted circle in CRKII represents putative binding site of
cSH3). In pCRKII, the inter-SH2-nSH3 linker (121–133) is
colored orange and the phosphorylation site (221–224) is cyan.
|
|
Figure 2.
Figure 2. Interdomain interactions in CRKII and pCRKII[1–228].
(a) Ribbon model of hydrophobic core of CRKII, between the
ISC and the SH domains, colored as in Figure 1. Side chains of
hydrophobic core are shown as sticks. (b) Interaction surfaces
between SH2 and nSH3 in CRKII (left), and between the C3G
peptide and nSH3 in CRKII (right). (c) Electrostatic surface
potential (blue, positive; red, negative) of SH2 in
pCRKII[1–228] and its recognition of 221-pYAQP-224 (shown as
stick model). (d) Electrostatic surface potential of nSH3 in
pCRKII[1–228] and its recognition of the inter-SH2-SH3 region
(stick model).
|
|
|
|
|
|
The above figures are
reprinted
by permission from Macmillan Publishers Ltd:
Nat Struct Mol Biol
(2007,
14,
503-510)
copyright 2007.
|
|
|
|
|
|
|
