Abstract
The APS, SH2-B and LNK proteins are adapters that activate and modulate receptor tyrosine kinase and JAK/STAT signaling. We now show that a conserved N-terminal domain mediates APS homodimerization. We determined the crystal structure of the dimerization domain at a resolution of 1.7 Å using bromide ion MAD phasing. Each molecule contributes two helices to a compact four-helix bundle having a bisecting-U topology. Its most conspicuous feature is a stack of interdigitated phenylalanine side chains at the domain core. These residues create a new motif we refer to as a 'phenylalanine zipper,' which is critical to dimerization. A newly developed bridging yeast tri-hybrid assay showed that APS dimerizes JAK2, insulin receptor and IGF1 receptor kinases using its SH2 and dimerization domains. Dimerization via the phenylalanine zipper domain provides a mechanism for activating and modulating tyrosine kinase activity even in the absence of extracellular ligands.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 968-974 |
| Number of pages | 7 |
| Journal | Nature Structural and Molecular Biology |
| Volume | 11 |
| Issue number | 10 |
| DOIs | |
| State | Published - Oct 2004 |
| Externally published | Yes |
Bibliographical note
Funding Information:We thank A. Saxena and the staff of beamline X12C at National Synchrotron Light Source and D. Frantz and J. Lee for helpful discussions and assistance. These studies were funded by US National Institutes of Health (NIH) grant R01 DK43123 (S.E.S.), Joslin Diabetes and Endocrinology Research Center NIH grant DK36836, fellowships from the Mary K. Iacocca Foundation (S.D. and Y.-I.C.), NIH (R29 DK09393 to E.D.W.), and Sankyo Foundation (M.N.), and the Helen and Morton Adler Chair in Structural Biology (S.E.S.).