Glutamate-receptor-interacting protein GRIP1 directly steers kinesin to dendrites

Abstract

In cells, molecular motors operate in polarized sorting of molecules, although the steering mechanisms of motors remain elusive. In neurons, the kinesin motor conducts vesicular transport such as the transport of synaptic vesicle components to axons and of neurotransmitter receptors to dendrites, indicating that vesicles may have to drive the motor for the direction to be correct. Here we show that an AMPA (alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate) receptor subunit--GluR2-interacting protein (GRIP1)--can directly interact and steer kinesin heavy chains to dendrites as a motor for AMPA receptors. As would be expected if this complex is functional, both gene targeting and dominant negative experiments of heavy chains of mouse kinesin showed abnormal localization of GRIP1. Moreover, expression of the kinesin-binding domain of GRIP1 resulted in accumulation of the endogenous kinesin predominantly in the somatodendritic area. This pattern was different from that generated by the overexpression of the kinesin-binding scaffold protein JSAP1 (JNK/SAPK-associated protein-1, also known as Mapk8ip3), which occurred predominantly in the somatoaxon area. These results indicate that directly binding proteins can determine the traffic direction of a motor protein.

A direct functional link between the multi-PDZ domain protein GRIP1 and the Fraser syndrome protein Fras1

“…Although the biological roles of multi-PDZ proteins are poorly understood, they might control the assembly of signaling complexes and the surface presentation and trafficking of transmembrane proteins [6][7][8] . Consistent with this function, GRIP1 associates with the kinesin heavy chain and is involved in synaptic vesicle transport by steering motor proteins to their targets 9 . To study the in vivo roles of GRIP1 and GRIP2, we inactivated the corresponding genes in mice ( Supplementary Fig.…”

Gain-of-function glutamate receptor interacting protein 1 variants alter GluA2 recycling and surface distribution in patients with autism

“…GRIP1 binds key proteins that regulate glutamatergic signaling, including liprin-α (28), PICK1 (29), KIF5 (30), and NEEP21 (31), and also uses the same PDZ4-6 to bind the GABA receptor-associated protein, gephyrin (32) (Fig. 1A).…”

A peptide zipcode sufficient for anterograde transport within amyloid precursor protein

“…Thus, other sequences may also encode the capacity to recruit kinesin and mediate transport. Kinesin-binding domains in JIP1 (37) and GRIP1 (35) have been identified, and these sequences await testing in motility assays such as we report here.…”