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PDBsum entry 1q2h
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Signaling protein
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PDB id
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1q2h
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References listed in PDB file
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Key reference
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Title
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A phenylalanine zipper mediates aps dimerization.
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Authors
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S.Dhe-Paganon,
E.D.Werner,
M.Nishi,
L.Hansen,
Y.I.Chi,
S.E.Shoelson.
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Ref.
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Nat Struct Mol Biol, 2004,
11,
968-974.
[DOI no: ]
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PubMed id
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Abstract
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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.
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Figure 1.
Figure 1. The APS/SH2-B/Lnk family. Schematic shows the
domain organization of human APS, SH2-B and Lnk. Structure-based
sequence alignment (below) is of the newly identified
dimerization domain (DD). N- and C-terminal helices of the
dimerization domain are identified above the sequences. Residues
buried within the domain core are indicated with markers:
phenylalanines within the zipper (Z) or paired at the ends of
the domain (F), alanines in the trough (A), and other core
residues (C).
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Figure 3.
Figure 3. Crystal structure of the APS dimerization domain.
Ribbon46 diagrams show the four-helix bundle formed from two
molecules, colored green or red, in an atypical bisecting-U
topology. Coils are brown and the  -turns
are blue. (a) Each molecule of the dimer contributes five
phenylalanines to the phenylalanine zipper. (b) Paired
phenylalanines also interact at the ends of the domain, and
three alanines form a trough on the surfaces of the N-terminal
helices.
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The above figures are
reprinted
by permission from Macmillan Publishers Ltd:
Nat Struct Mol Biol
(2004,
11,
968-974)
copyright 2004.
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