title: A phenylalanine zipper mediates APS dimerization.
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 A 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.
authors.affiliation: Joslin Diabetes Center and Department of Medicine, Harvard Medical School, Boston, Massachusetts 02215, USA.
authors.forename: Sirano
authors.initials: S
authors.lastname: Dhe-Paganon
authors.forename: Eric D
authors.initials: ED
authors.lastname: Werner
authors.forename: Masahiro
authors.initials: M
authors.lastname: Nishi
authors.forename: Lone
authors.initials: L
authors.lastname: Hansen
authors.forename: Young-In
authors.initials: YI
authors.lastname: Chi
authors.forename: Steven E
authors.initials: SE
authors.lastname: Shoelson
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport / Q000737:chemistry / Q000502:physiology*; D019281:Dimerization; D006801:Humans; D010649:Phenylalanine / Q000737:chemistry / Q000502:physiology*; D011487:Protein Conformation
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; C107249:SH2B2 protein, human; D010649:Phenylalanine