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* Division of Immunochemistry and
Division of Molecular Biophysics, Deutsches Krebsforschungszentrum, D-69120 Heidelberg, Germany
1Correspondence: Division of Immunochemistry Deutsches Krebsforschungszentrum Im Neuenheimer Feld 280 69120 Heidelberg, Germany. E-mail: W.Droege{at}dkfz-heidelberg.de
Signaling by insulin requires autophosphorylation of the insulin
receptor kinase (IRK) at Tyr1158, Tyr1162, and Tyr1163. Earlier
experiments with 32P-
-ATP indicated that the
nonphosphorylated IRK (IRK-0P) is relatively inactive, and
crystallographic data indicated that the ATP binding site of IRK-0P is
blocked by its activation loop. We now show that phosphocreatine (PCr)
in combination with hydrogen peroxide serves as an alternative
phosphate donor and that ATP and PCr use distinct binding sites.
Whereas phosphorylation of the IRK by ATP is inhibited by the
nonhydrolyzable competitor adenylyl-imidodiphosphate, phosphorylation
by PCr is enhanced. The IRK mutant Tyr1158Phe showed no
phosphorylation with PCr but almost normal phosphorylation with ATP,
whereas Tyr1162Phe was phosphorylated well with PCr but less then
normal with ATP. 3-Dimensional models of IRK-0P revealed that the
conversion of any of the four cysteine residues 1056, 1138, 1234, and
1245 into sulfenic acid produces structural changes that bring Tyr1158
into close contact with Asp1083 and render the well-known catalytic
site at Asp1132 and Tyr1162 accessible from a direction that differs
from the known ATP binding site. The mutant Cys1138Ala, in contrast,
showed relatively inaccessible catalytic sites and weak catalytic
activity in functional experiments. Taken together, these findings
indicate that `redox priming' of the IRK facilitates its
autophosphorylation by PCr in the activation loop.—Schmid, E.,
Hotz-Wagenblatt, A., Hack, V., Dröge, W. Phosphorylation of the
insulin receptor kinase by phosphocreatine in combination with hydrogen
peroxide: the structural basis of redox priming.
Key Words: insulin responsiveness • redox regulation • signal transduction • tyrosine kinase
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