Molecular Structure of CD2AP in Layman Terms
CD2AP (CD2-associated protein) is a multidomain scaffolding protein that forms a tetramer (four-part structure) with a central coiled-coil domain surrounded by four symmetrical arrangements of three SH3 domains each, creating a spherical structure that allows it to simultaneously bind to multiple protein targets. 1
Overall Structure and Organization
- CD2AP is a tetramer (four protein units joined together) that forms a roughly spherical, loosely packed structure 1
- The protein has a central coiled-coil domain that serves as the tetramer interface, connecting the four individual units 1
- Around this central core, four symmetry-related motifs extend outward, each containing three globular domains 1
Domain Composition
- CD2AP contains three SH3 (Src Homology 3) domains positioned in the N-terminal region of the protein 2
- These SH3 domains are labeled as SH3-A, SH3-B, and SH3-C (or SH3-1, SH3-2, and SH3-3) 3
- Each SH3 domain has a typical structure found in other SH3 domains, including binding sites for recognizing polyproline sequences 2
- The tetrameric structure exposes all 12 SH3 domains (3 from each of the 4 protein units), allowing simultaneous binding to multiple targets 1
Functional Binding Properties
- The first two SH3 domains (SH3-1 and SH3-2) generally have similar binding characteristics and specificities 3
- The third SH3 domain (SH3-3) binds more weakly to most peptide ligands but can recognize unusually extended sequences in certain proteins like ALIX 3
- The preferred binding motif for CD2AP SH3 domains is Px(P/A)xPR, as determined by high-resolution crystal structures 3
Unique Structural Features
- CD2AP contains a novel binding motif LXHXTXXRPK(X)6P that enables interaction with actin-capping protein CP 4
- The N-terminal SH3 domain of CD2AP is one of the most stable SH3 domains studied, due to an extensive network of intra-molecular interactions 5
- This high stability is crucial for maintaining the proper conformation needed to establish interactions with natural targets 5
Biological Significance
- The spatial organization of CD2AP's structure is critical for its function as an adaptor protein 1
- The exposed binding sites of all SH3 domains allow CD2AP to interact with multiple targets simultaneously, including CD2, nephrin, c-Cbl, and podocin 2
- This structural arrangement enables CD2AP to play its essential role in kidney function, particularly in maintaining the filtration barrier in glomerular podocytes 1