Src Homology 3 (SH3) domain
References:
High-resolution crystal structures of tyrosine kinase SH3 domains complexed
with proline-rich peptides. Musacchio, A., Saraste, M., Wilmanns, M. (1994)
Nature Struct. Biol. 1, 546-551.
Structure and function of the SH3 domain. Musacchio, A., Wilmanns, M., Saraste,
M. (1994) Prog. Biophys. molec.Biol. 61, 283-297.
Different folding transitions states could result in the
same native structure. Viguera, A.R., Serrano, L. & Wilmanns,. M.
(1996), submitted.
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Src Homology 3 (SH3) domains are small modular domains of 50-70 residues
that are found in many proteins that mediate protein-protein interactions
important in cytoskeletal architecture and intracellular tyrosine kinase
mediated signalling (Musacchio et al., 1994b; Pawson, 1995; Cohen et al.,
1995). The signals are transduced through binding to ligand proteins that
contain proline-rich motifs (Ren et al., 1993; Gout et al., 1993; Yu et
al., 1994). The 3D structure of SH3 consists of two perpendicular, antiparallel
b-sheets (Musacchio et al., 1992; several other NMR and crystal structures
were solved subsequently). T
The peptide binding site was identified as a surface mostly composed by
aromatic residues (Musacchio et al., 1992; Yu et al., 1992; Yu et al., 1994).
We solved two SH3 : decapeptide complex structures to establish a structural
basis of the protein-protein interactions mediated by SH3 domains. The structures
of Abl-SH3 : (APTMPPPLPP) and Fyn-SH3 : (PPAYPPPPVP) were solved by molecular
replacement at 2.0 Å and 2.3 Å resolution, respectively (Musacchio
et al., 1994a). Both synthetic peptides were derived from the known ligand
proteins 3BP-1 and 3BP-2 (Ren et al., 1993). The peptides bind into three
conserved binding cavities of each SH3 domain in an almost identical manner
(Figure 4). Residues 4-10 of these peptide are in extended proline type-II
conformation which is unique through its almost perfect 3-fold symmetry.
The lack of specific side chain interactions might serve as explanation
for the moderate binding affinities (Ren et al., 1993).
An interesting feature of the Fyn-SH3 complex structure is the 2:1 stoichiometry
of Fyn-SH3 : peptide (Musacchio et al., 1994a). In this crystal form the
peptide binds two symmetry related SH3 domains in opposite orientations.
In the subsequently solved crystal structure of the Sem5-SH3 : (PPPVPPRRR)
complex the peptide was bound in the opposite orientation (Lim et al., 1994)
compared to the Abl-SH3 complex. A more recent crystal structure of the
cCrk-SH3 : (PPPALPPKR) complex showed that determinants of binding specificity
and affinity are specific polar side-chain interactions between SH3 domains
and the ligand protein (Wu et al., 1995). The orientation of the proline
rich motif is determined by the location of these side chains with respect
to the proline rich motif in the SH3 ligand proteins.
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