Pick1

Among the earliest PKC-interacting proteins to be identified in a yeast two-hybrid screen was PICK1 (protein interacting with C kinase 1) (Staudinger et al. 1995). PICK1 bound PKC-a with high affinity and yet did not become phosphorylated upon PKC-a activation, suggesting that its role was to position PKC-a near key substrates within the cell. Sequence and 3D structural analysis of PICK1 revealed that in addition to binding PKC, it contained a PDZ domain and a BAR domain, providing further clues to its overall function (Tarricone et al. 2001; Peter et al. 2004; Xu and Xia 2007). PDZ domains have emerged in recent years as canonical protein-protein interaction domains that typically recognize a four-residue motif at the C-terminus of its binding partners (Dev 2004). The PDZ domain of PICK1 appears to recognize its own preferred C-terminal motif, which does not fit neatly into the original type-1 and type-2 PDZ recognition motif classification (Madsen et al. 2005). In contrast, BAR domains oligomerize into a coiled-coil stabilized boomerang-shaped structure that is thought to recognize and/or dictate the curvature of membranes (Tarricone et al. 2001). As such, BAR domains are thought to play critical roles in endocytosis and tubulation of membranes. The BAR domain of PICK1 was initially not recognized to be a BAR domain based only upon sequence analysis. When the crystal structure of a BAR-like domain from arfaptin (a homolog of PICK1) was compared to amphiphysin, another well-characterized tubulating protein, it was clear that both formed boomerang-shaped oligomers with lysine/ arginine residues located at critical positions for interacting with membrane surfaces (Tarricone et al. 2001; Peter et al. 2004; Xu and Xia 2007) Thus, with low sequence homology, but high structural homology, PICK1 was deemed to contain a membrane-curvature-sensing BAR domain. PICK1 is the only protein known to contain both a PDZ domain and a BAR domain, suggesting a unique role in organizing the protein machinery involved in endocytosis, membrane traffic (Wang et al. 2003) and synaptic plasticity (Gardiner et al. 2005). PKC-a is recruited to these complexes by binding its C-terminus to the PDZ domain of PICK1 (Staudinger et al. 1997; Dev et al. 2004), with additional contributions from lipid-binding domains on PKC-a that are also sensitive to membrane curvature and/or the presence of non-bilayer structures (Jimenez-Monreal et al. 1999).

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