Structural and biochemical evidence for an autoinhibitory role for tyrosine 984 in the juxtamembrane region of the insulin receptor.

J Biol Chem 2003 Jul 21;278(28):26007-14. Epub 2003 Apr 21.

Skirball Institute of Biomolecular Medicine and Department of Pharmacology, New York University School of Medicine, New York, New York 10016, USA.

Tyrosine 984 in the juxtamembrane region of the insulin receptor, between the transmembrane helix and the cytoplasmic tyrosine kinase domain, is conserved among all insulin receptor-like proteins from hydra to humans. Crystallographic studies of the tyrosine kinase domain and proximal juxtamembrane region reveal that Tyr-984 interacts with several other conserved residues in the N-terminal lobe of the kinase domain, stabilizing a catalytically nonproductive position of alpha-helix C. Steady-state kinetics measurements on the soluble kinase domain demonstrate that replacement of Tyr-984 with phenylalanine results in a 4-fold increase in kcat in the unphosphorylated (basal state) enzyme. Moreover, mutation of Tyr-984 in the full-length insulin receptor results in significantly elevated receptor phosphorylation levels in cells, both in the absence of insulin and following insulin stimulation. These data demonstrate that Tyr-984 plays an important structural role in maintaining the quiescent, basal state of the insulin receptor. In addition, the structural studies suggest a possible target site for small molecule activators of the insulin receptor, with potential use in the treatment of noninsulin-dependent diabetes mellitus.

Download full-text PDF

Source
http://dx.doi.org/10.1074/jbc.M302425200DOI Listing
July 2003
6 Reads

Publication Analysis

Top Keywords

insulin receptor
20
kinase domain
16
juxtamembrane region
12
984 juxtamembrane
8
insulin
8
tyrosine 984
8
tyrosine kinase
8
basal state
8
region insulin
8
receptor
6
mutation tyr-984
4
catalytically nonproductive
4
enzyme mutation
4
state enzyme
4
nonproductive position
4
tyr-984 full-length
4
stabilizing catalytically
4
receptor phosphorylation
4
phosphorylation levels
4
elevated receptor
4

References

(Supplied by CrossRef)

J. Biol. Chem. 1991

Mol. Cell. Biol. 1995

Similar Publications