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PDBsum entry 1z57
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References listed in PDB file
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Key reference
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Title
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Kinase domain insertions define distinct roles of clk kinases in sr protein phosphorylation.
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Authors
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A.N.Bullock,
S.Das,
J.E.Debreczeni,
P.Rellos,
O.Fedorov,
F.H.Niesen,
K.Guo,
E.Papagrigoriou,
A.L.Amos,
S.Cho,
B.E.Turk,
G.Ghosh,
S.Knapp.
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Ref.
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Structure, 2009,
17,
352-362.
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PubMed id
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Abstract
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Splicing requires reversible phosphorylation of serine/arginine-rich (SR)
proteins, which direct splice site selection in eukaryotic mRNA. These
phosphorylation events are dependent on SR protein (SRPK) and cdc2-like kinase
(CLK) families. SRPK1 phosphorylation of splicing factors is restricted by a
specific docking interaction whereas CLK activity is less constrained. To
understand functional differences between splicing factor targeting kinases, we
determined crystal structures of CLK1 and CLK3. Intriguingly, in CLKs the SRPK1
docking site is blocked by insertion of a previously unseen helix alphaH. In
addition, substrate docking grooves present in related mitogen activating
protein kinases (MAPKs) are inaccessible due to a CLK specific beta7/8-hairpin
insert. Thus, the unconstrained substrate interaction together with the
determined active-site mediated substrate specificity allows CLKs to complete
the functionally important hyperphosphorylation of splicing factors like
ASF/SF2. In addition, despite high sequence conservation, we identified
inhibitors with surprising isoform specificity for CLK1 over CLK3.
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