Protein interacting with C kinase 1 (PICK1) is a peripheral membrane protein involved in protein trafficking, a function that has been well characterized in neurons. Here, we report that male mice deficient in PICK1 are infertile and have a phenotype resembling the human disease globozoospermia. The primary defect in the testes of Pick1-knockout mice was fragmentation of acrosomes in the early stages of spermiogenesis. This fragmentation was followed by defects in nuclear elongation and mitochondrial sheath formation, leading to round-headed sperm, reduced sperm count, and severely impaired sperm motility. We found that PICK1 interacted with Golgi-associated PDZ-and coiled-coil motif-containing protein (GOPC) and the primary catalytic subunit of protein kinase 2 (CK2α′), proteins whose deficiencies lead to globozoospermia in mice. PICK1 was highly expressed in round spermatids and localized to Golgi-derived proacrosomal granules. GOPC colocalized with PICK1 in the Golgi region and facilitated formation of PICK1-positive clusters. Furthermore, there was an increase in apoptosis in the seminiferous tubules of Pick1 -/-mice, a phenotype also seen in CK2α′-deficient mice. Our results suggest that PICK1 is involved in vesicle trafficking from the Golgi apparatus to the acrosome and cooperates with other proteins such as GOPC and CK2α′ in acrosome biogenesis. IntroductionProtein interacting with C kinase 1 (PICK1) is a peripheral membrane protein involved in protein trafficking. PICK1 was initially identified as a protein kinase C-interacting protein from a yeast two-hybrid screen (1). Subsequently, many proteins have been found to interact with PICK1 (2). The majority of these proteins are membrane proteins, such as glutamate receptors, dopamine transporter, Eph receptors, and acid-sensing ion channels (3-8). These interactions usually occur between the C termini of the membrane proteins and PICK1's postsynaptic density 95, discs large, and zonula occludens-1 (PDZ) domain, a well-characterized protein-protein interaction module. In most cases, PICK1 regulates the subcellular localization or cell-surface expression of its PDZ domain-binding partners.Studies of PICK1's role in α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor trafficking have provided much information that helps us to understand PICK1's function. The AMPA receptor is a subtype of glutamate receptor that mediates the majority of excitatory synaptic transmission in the brain (9). The role of PICK1 has been extensively studied in AMPA receptor trafficking because of its implication in synaptic plasticity, a cellular model of learning and memory (10). PICK1 was found to interact specifically with the C termini of AMPA receptor subunits

PICK1 and ICA69, proteins containing a BAR domain, regulate the biogenesis and maturation of insulin granules in mice.

The trafficking of AMPA-type glutamate receptors to and from synapses is an important mechanism underlying synaptic plasticity, a cellular model of learning and memory. PICK1 (protein interacts with C-kinase 1) is a peripheral membrane protein that interacts with AMPA receptors and regulates their trafficking.

Zonula occludens (ZO)-1 is a multi-domain scaffold protein known to have critical roles in the establishment of cell-cell adhesions and the maintenance of stable tissue structures through the targeting, anchoring, and clustering of transmembrane adhesion molecules and cytoskeletal proteins. Here, we report that ZO-1 directly binds to MRCKb, a Cdc42 effector kinase that modulates cell protrusion and migration, at the leading edge of migrating cells. Structural studies reveal that the binding of a b hairpin from GRINL1A converts ZO-1 ZU5 into a complete ZU5-fold. A similar interaction mode is likely to occur between ZO-1 ZU5 and MRCKb. The interaction between ZO-1 and MRCKb requires the kinase to be primed by Cdc42 due to the closed conformation of the kinase. Formation of the ZO-1/MRCKb complex enriches the kinase at the lamellae of migrating cells. Disruption of the ZO-1/MRCKb complex inhibits MRCKb-mediated cell migration. These results demonstrate that ZO-1, a classical scaffold protein with accepted roles in maintaining cell-cell adhesions in stable tissues, also has an active role in cell migration during processes such as tissue development and remodelling.