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Figure 1.
Figure 1. Structure of SAP and the Location of Missense
Mutations Identified in XLP Patients(A) Ribbon diagram showing
the SAP/SLAM pY281 complex. The bound phosphopeptide is shown in
a stick representation (yellow). Selected SAP residues that form
the binding site are shown in blue. Elements of secondary
structure are labeled using the standard SH2 domain nomenclature
([8]). Note that the pY −3 to pY −1 residues of the peptide
make a parallel β sheet interaction with strand βD; the side
chains of these peptide residues make hydrophobic contacts with
Tyr-50, Ile-51, and Tyr-52 in strand βD, and with Leu-21. Thr
(pY −2) in the peptide hydrogen bonds with Glu-17 and with a
buried water molecule. The phosphotyrosine is coordinated in a
manner similar to that observed in the N-terminal domain of
SHP-2, and as in SHP-2, the phosphate group is rotated
“above” the plane of the phosphotyrosine ring.
Interestingly, arginine 13 (at position αA2), which is
conserved in almost all SH2 domains and usually contributes to
phosphotyrosine coordination, does not participate in phosphate
binding in the SAP complex. Instead, arginine 55 (βD6) hydrogen
bonds with the phosphate group. C-terminal to phosphotyrosine,
Val(pY +3) binds in a mostly hydrophobic cleft.(B) Point
mutations identified in XLP patients cluster along the
peptide-binding site and at the back of the domain. Mutations
that would be expected to directly disrupt the
phosphotyrosine-binding pocket are shown in green, and those
that would disrupt C-terminal interactions in magenta. The
remaining mutations (gold) are remote from the peptide-binding
surface and may destabilize the folded protein (see text).(C)
Structure-based sequence comparisons of human SAP, murine EAT-2,
and other SH2 domains. Elements of secondary structure are
indicated above the alignment. Numbering corresponds to human
SAP. The black diamonds indicate the mutations illustrated in
(B).
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