PDBsum entry 1eg3

Structural protein

PDB id: 1eg3

Contents

Protein chain

260 a.a. *

Waters ×266

* Residue conservation analysis

References listed in PDB file

Key reference

Title

Structure of a ww domain containing fragment of dystrophin in complex with beta-Dystroglycan.

Authors

X.Huang, F.Poy, R.Zhang, A.Joachimiak, M.Sudol, M.J.Eck.

Ref.

Nat Struct Biol, 2000, 7, 634-638. [DOI no: 10.1038/77923]

PubMed id

10932245

Abstract

Dystrophin and beta-dystroglycan are components of the dystrophin-glycoprotein complex (DGC), a multimolecular assembly that spans the cell membrane and links the actin cytoskeleton to the extracellular basal lamina. Defects in the dystrophin gene are the cause of Duchenne and Becker muscular dystrophies. The C-terminal region of dystrophin binds the cytoplasmic tail of beta-dystroglycan, in part through the interaction of its WW domain with a proline-rich motif in the tail of beta-dystroglycan. Here we report the crystal structure of this portion of dystrophin in complex with the proline-rich binding site in beta-dystroglycan. The structure shows that the dystrophin WW domain is embedded in an adjacent helical region that contains two EF-hand-like domains. The beta-dystroglycan peptide binds a composite surface formed by the WW domain and one of these EF-hands. Additionally, the structure reveals striking similarities in the mechanisms of proline recognition employed by WW domains and SH3 domains.

Figure 1.
Figure 1. Structure of the dystrophin - -dystroglycan complex. a, Ribbon diagram showing the overall organization of the dystroglycan binding region of dystrophin. The WW domain is colored yellow, the first EF-hand domain green, the second EF-hand domain blue, and additional helices gold. The -dystroglycan peptide (white) extends across the first EF-hand and the WW domain. Elements of secondary structure, the N- and C-termini of the protein, and peptide are labeled. b, Molecular surface of the DBR, colored as in (a). The surface of residues in the WW domain and EF-hand that contact the peptide are shaded bright yellow and dark green, respectively, to highlight the binding surface. Peptide residues Pro 889 -Tyr 892 constitute the PPxY motif. All Pro residues in the peptide are in the trans conformation; those in the PPxY motif form a single turn of polyproline II helix. c , Detailed view of dystrophin - -dystroglycan recognition. The thin red lines indicate hydrogen bonds. The peptide makes six hydrogen bonds directly to the DBR domain, and an additional six through bridging water molecules (indicated by red spheres).

Figure 3.
Figure 3. Stereo views showing the binding mode of Pro residues by the WW domain and comparison to that observed in SH3 domains. a, Electron density map at the interface between the -dystroglycan peptide and the WW and EF-hand domains. The 2F[o] - F[ c] map is contoured at 1.3 and was calculated using data to 1.9 Å resolution. The dystrophin domains and the peptide are colored as in Fig. 1. Note the interactions of peptide Pro residues with the 'aromatic cradle' formed by Tyr 3072 and Trp 3083. Residues Trp 3061 and Pro 3086 are highly conserved in WW domains and form the hydrophobic buckle on the underside of the domain. b, Superposition of the dystrophin aromatic cradle with a similar recognition element in the Abl SH3 domain20. The superposition was calculated using only the proline-rich peptides (residues 887 -890 in the -dystroglycan peptide, with residues C4 -C7 in the Abl SH3 -peptide complex). Thin black lines indicate similar hydrogen bond and hydrophobic interactions. Note that the geometry of interaction with the Trp residue is essentially identical in the two structures, including the contact of the Pro with the Trp ring, and the hydrogen bond to the Trp from the carbonyl group of the 'P-2' residue (the residue preceeding the first proline by two positions). The second Pro residue (Pro 890 in -dystroglycan) makes a van der Waals contact to Ser 3066 that is similar to that made to a Phe ring in the Abl structure. The interaction of Pro 890 with the surface of Tyr 3072 is more divergent; the corresponding surface is formed by a Pro and a Tyr in the SH3 domain. Both SH3 and WW domains have been shown to recognize non-natural N-substituted amino acids (in addition to Pro) at particular positions33; the site occupied by Pro 890 is such a position, and it would likely accommodate small hydrophobic N-substituted residues.

The above figures are reprinted by permission from Macmillan Publishers Ltd: Nat Struct Biol (2000, 7, 634-638) copyright 2000.