Cargo Recognition

Transmembrane cargo proteins do not directly bind to molecular motors but instead use adaptor/scaffolding polypeptides or protein complexes for cargo recognition and binding6,9,12-14. For instance the interaction between KIF17 and cargo vesicles that contain NMDA-type glutamate receptors is mediated by a triple complex of mLIN-family proteins (for: mammaliam homolog of C. elegans lineage abnormal) that contains mLIN10 (MINT1), mLIN2 (CASK), and mLIN7 (VELIS/MALS). The microtubule-associated motor binds to the cytoplasmic LIN10 through a PDZ domain-mediated interaction. The vesicular NR2B subunit of NMDA receptors interacts through its carboxy (C)-terminal tail with cytoplasmic mLIN7. To connect the cargo vesicle with its transport track, mLIN2 then functions as a linker between the mLIN10-motor complex and the mLIN7-receptor-vesicle complex, thereby generating a large complex that transports NR2B containing receptors toward postsynaptic sites12. Evidence that these interactions are important for in vivo function comes from a study in which transgenic overexpression of the motor protein KIF17 enhances NR2B-mediated spatial and working memory in mice15. All three mLIN family proteins contain PDZ domains, which are not involved to bind each other, but to recruit other proteins to the complex.

It has been discussed that kinesin motor proteins consist of a large heavy chain represented by head, neck, stalk and tail domains and also binds accessory light chains. As kinesin light chain KLC binds to the C-terminal tail of KIF5, the question arises whether cargoes bind to heavy chain sequences of KIF5 or to KLC. Different studies in neurons, including loss-of-function experiments, currently suggest that cargoes bind both to the C-terminal tail of KIF5 as well as to KLC; however binding to KLC tends to be used for transporting cargoes to axons, whereas binding to the C-terminal tail of KIF5 seems to be used for directing cargoes to dendrites6. This view seems to be true not only for protein transport, since also granules that contain calmodulin-dependent protein kinase II (CaMKII)

or ARC mRNAs for transport to dendrites, directly bind to the C-terminal tail of KIF516'17.

Also if cargo binds kinesin through KLCs, the interaction of cargo and KLC is often not direct. Scaffolding proteins of the c-Jun N-terminal kinase (JNK) signaling pathway, JIP1, JIP2 or JIP3, are abundant at neuronal processes and synaptic junctions and mediate cargo binding to KLCs. For instance, JIP1 is thought to bridge the interaction of KLC with the amyloid precursor protein APP. The phosphotyrosine-binding domain of JIP1 binds APP and JIP1 is required for the interaction of APP with KLC18,19.

In contrast to kinesins, the recognition of cargoes of cytoplasmic dynein is currently barely understood. The dynein-associated protein complex dynactin contains a short filament of actin-related protein ARP1. In addition, dynactin binds to p150Glued and dynamitin7. Although dynamitin seems to be critical for cargo binding to the dynein complex, cargo elements bind to different components of the complex. During ER to Golgi trafficking, the Golgi-associated spectrin isoform PIII spectrin directly binds to ARP120. However, the transmembrane protein rhodopsin and the scaffold protein gephyrin couple to cytoplasmic dynein through binding to the dynein light chains TCTEX1 and DLC1/DLC2, respectively8,21.

In general, a large number of cellular molecules are subject of transport by a limited number of molecular motors (Table 1). Therefore, accessory intermediate and light chains, as well as adaptor/scaffolding proteins allow a large combination of individual and unique transport complexes and thereby contribute to the specificity of cargo recognition and transport to specific subcellular domains.

Anxiety Gephyrin
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