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PDBsum entry 2qoq
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References listed in PDB file
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Key reference
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Title
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Autoregulation by the juxtamembrane region of the human ephrin receptor tyrosine kinase a3 (epha3).
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Authors
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T.L.Davis,
J.R.Walker,
P.Loppnau,
C.Butler-Cole,
A.Allali-Hassani,
S.Dhe-Paganon.
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Ref.
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Structure, 2008,
16,
873-884.
[DOI no: ]
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PubMed id
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Abstract
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Ephrin receptors (Eph) affect cell shape and movement, unlike other receptor
tyrosine kinases that directly affect proliferative pathways. The kinase domain
of EphA3 is activated by ephrin binding and receptor oligomerization. This
activation is associated with two tyrosines in the juxtamembrane region; these
tyrosines are sites of autophosphorylation and interact with the active site of
the kinase to modulate activity. This allosteric event has important
implications both in terms of understanding signal transduction pathways
mediated by Eph kinases as well as discovering specific therapeutic ligands for
receptor kinases. In order to provide further details of the molecular mechanism
through which the unphosphorylated juxtamembrane region blocks catalysis, we
studied wild-type and site-specific mutants in detail. High-resolution
structures of multiple states of EphA3 kinase with and without the juxtamembrane
segment allowed us to map the coupled pathway of residues that connect the
juxtamembrane segment, the activation loop, and the catalytic residues of the
kinase domain. This highly conserved set of residues likely delineates a
molecular recognition pathway for most of the Eph RTKs, helping to characterize
the dynamic nature of these physiologically important enzymes.
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Figure 2.
Figure 2. Overall Structure of EphA3 Kinase
All
molecular graphics figures were generated using PyMOL unless
noted.
(A) Cartoon representation of the EphA3 JMKIN base
ANP structure. The structure is shown in forest green and in
cartoon representation. Secondary structure elements and regions
discussed in the test are labeled. Regions of disorder are
indicated with dashed lines. This structure was chosen because
it represents the highest degree of order modeled for all the
EphA3 structures.
(B) Ribbon representation of JMKIN base
ANP overlaid with EphB2 in pink (1JPA). Alignment over all atoms
yields an rmsd of less than 1Å for all structures; key
regions of structural difference occur in the N-terminal lobe,
centered on the JMS and the AL, along with slight differences in
the β1-G loop-β2 region.
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Figure 4.
Figure 4. The Linker Between the Kinase and SAM Domains Binds
into a Complementary Pocket on the C-terminal Lobe of the Kinase
Domain
An electrostatic surface was generated using APBS
(Baker et al., 2001) using a gradient from −10 to 10 keT.
Shown in cartoon and stick representation is the model for KIN
ANP in firebrick red; this model contains the most ordered
linker region comprising residues 885–906. Highlighted is the
complementary surface made up by Tyr841, Leu901, and Leu903.
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The above figures are
reprinted
by permission from Cell Press:
Structure
(2008,
16,
873-884)
copyright 2008.
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