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Crystal structure of a complex between protein tyrosine phosphatase 1B and the insulin receptor tyrosine kinase

Shiqing Li1, Rafael S Depetris, David Barford

  • 1Structural Biology Program, Skirball Institute of Biomolecular Medicine and Department of Pharmacology, New York University School of Medicine, New York, New York 10016, USA.

Structure (London, England : 1993)
|November 8, 2005
PubMed

Insights

Protein tyrosine phosphatase 1B (PTP1B) selectively binds the insulin receptor (IR) through a non-catalytic interaction. This structural insight into PTP1B-IR complex formation may explain PTP1B

Area of Science:

  • Biochemistry
  • Structural Biology
  • Molecular Endocrinology

Background:

  • Protein tyrosine phosphatase 1B (PTP1B) is a key negative regulator of insulin receptor signaling.
  • The molecular mechanisms underlying PTP1B's specificity for the insulin receptor (IR) over other receptor tyrosine kinases remain largely unelucidated.

Purpose of the Study:

  • To determine the structural basis for the specific interaction between PTP1B and the insulin receptor.
  • To investigate the potential non-catalytic mechanisms governing PTP1B recruitment to the insulin receptor.

Main Methods:

  • X-ray crystallography was employed to obtain a 2.3 Å resolution structure of the PTP1B catalytic domain (trapping mutant) complexed with the phosphorylated insulin receptor kinase domain (IRK).

Main Results:

  • The crystal structure revealed that PTP1B binds to the insulin receptor kinase domain on the opposite side of the activation loop.
  • Phosphorylated activation loops of the insulin receptor were sequestered within an IRK dimer interface, suggesting a non-substrate binding interaction.
  • Two PTP1B-IRK complexes were observed in the crystallographic asymmetric unit, interacting via the IRK dimer interface.

Conclusions:

  • The study provides structural evidence for a non-catalytic mode of interaction between PTP1B and the insulin receptor.
  • This non-catalytic binding mechanism may be crucial for the selective recruitment of PTP1B to the insulin receptor, influencing insulin signaling.

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