5WRM

Mu2 subunit of the clathrin adaptor complex AP2 in complex with IRS-1 Y658 peptide

Summary for 5WRM

• Entry DOI: 10.2210/pdb5wrm/pdb
• Related: 5WRK 5WRL
• Descriptor: AP-2 complex subunit mu, Insulin receptor substrate 1 (3 entities in total)
• Functional Keywords: endocytosis, clathrin adaptor ap-2 complex subunit, peptide complex
• Biological source: Rattus norvegicus (Rat); More
• Total number of polymer chains: 2
• Total formula weight: 32701.39

Authors

Yoneyama, Y.,Niwa, H.,Umehara, T.,Yokoyama, S.,Hakuno, F.,Takahashi, S. (deposition date: 2016-12-02, release date: 2017-12-06, Last modification date: 2023-11-08)

Primary citation

Yoneyama, Y.,Lanzerstorfer, P.,Niwa, H.,Umehara, T.,Shibano, T.,Yokoyama, S.,Chida, K.,Weghuber, J.,Hakuno, F.,Takahashi, S.I.
IRS-1 acts as an endocytic regulator of IGF-I receptor to facilitate sustained IGF signaling
Elife, 7:-, 2018

PubMed Abstract: Insulin-like growth factor-I receptor (IGF-IR) preferentially regulates the long-term IGF activities including growth and metabolism. Kinetics of ligand-dependent IGF-IR endocytosis determines how IGF induces such downstream signaling outputs. Here, we find that the insulin receptor substrate (IRS)-1 modulates how long ligand-activated IGF-IR remains at the cell surface before undergoing endocytosis in mammalian cells. IRS-1 interacts with the clathrin adaptor complex AP2. IRS-1, but not an AP2-binding-deficient mutant, delays AP2-mediated IGF-IR endocytosis after the ligand stimulation. Mechanistically, IRS-1 inhibits the recruitment of IGF-IR into clathrin-coated structures; for this reason, IGF-IR avoids rapid endocytosis and prolongs its activity on the cell surface. Accelerating IGF-IR endocytosis via IRS-1 depletion induces the shift from sustained to transient Akt activation and augments FoxO-mediated transcription. Our study establishes a new role for IRS-1 as an endocytic regulator of IGF-IR that ensures sustained IGF bioactivity, independent of its classic role as an adaptor in IGF-IR signaling.

PubMed: 29661273
DOI: 10.7554/eLife.32893

Experimental method

X-RAY DIFFRACTION (2.597 Å)