The kinesin superfamily protein KIF17: one protein with many functions

Abstract

Kinesins are ATP-dependent molecular motors that carry cargos along microtubules, generally in an anterograde direction. They are classified into 14 distinct families with varying structural and functional characteristics. KIF17 is a member of the kinesin-2 family that is plus end-directed. It is a homodimer with a pair of head motor domains that bind microtubules, a coiled-coil stalk, and a tail domain that binds cargos. In neurons, KIF17 transports N-methyl-D-aspartate receptor NR2B subunit, kainate receptor GluR5, and potassium Kv4.2 channels from cell bodies exclusively to dendrites. These cargos are necessary for synaptic transmission, learning, memory, and other functions. KIF17's interaction with NXF2 enables the transport of mRNA bidirectionally in dendrites. KIF17 or its homolog OSM-3 also mediates intraflagellar transport of cargos to the distal tips of flagella or cilia, thereby aiding in ciliogenesis. In many invertebrate and vertebrate sensory cells, KIF17 delivers cargos that contribute to chemosensory perception and signal transduction. In vertebrate photoreceptors, KIF17 is necessary for outer segment development and disc morphogenesis. In the testis, KIF17 (KIF17b) mediates microtubule-independent delivery of ACT from the nucleus to the cytoplasm and microtubule-dependent transport of Spatial-ε, both are presumably involved in spermatogenesis. KIF17 is also implicated in epithelial polarity and morphogenesis, placental transport and development, and the development of specific brain regions. The transcriptional regulation of KIF17 has recently been found to be mediated by nuclear respiratory factor 1 (NRF-1), which also regulates NR2B as well as energy metabolism in neurons. Dysfunctions of KIF17 are linked to a number of pathologies.

Keywords: NR2B transport; ciliary transport; kinesin-2 family; microtubules; transcriptional control.

Figure 1

Phylogenetic tree showing the relationship of kinesin 2 family heavy chains discussed in this review. The tree was constructed with the Clustal W method of multi-sequence alignment using DNASTAR software. A more complete analysis of all kinesin heavy chains including the kinesin 2 family can be seen in [6] and the associated website. The tree shows evolutionary distance measured as substitutions per 100 amino acids using the full-length sequences of each heavy chain. Included are the heterotrimeric heavy chains KIF3A and KIF3B from Danio rerio and Mus musculus. The comparable heavy chains, KLP-20 and KLP-11, from Caenorhabditis elegans, and FLA10/KHP1 and FLA8 from Chlamydomonas reinhardtii are included as well. FLA8 is the heavy chain binding partner of FLA10 [58]. The homodimeric heavy chains include KIF17 from D. rerio and M. musculus, OSM-3 from C. elegans, and KIN5 from Tetrahymena thermophila. The dashed line associated with KIN5 represents a negative branch length caused by averaging during the alignment. A homodimeric kinesin 2 motor has not been described in C. reinhardtii.

Figure 2

Diagrammatic representation of the KIF17 homodimer in its active (A) and auto-inhibited (B) configurations. In B, the cargo binding tail domain (green) associates with the microtubule binding ATPase head domain (blue). Cargo binding could involve intermediate adaptor complexes, as in the case of NR2B trafficking in dendrites or IFT trafficking in cilia. However, in the testis, ACT binds to an intermediate domain (C) within the stalk rather than the tail in a regulatory event that occurs independently of KIF17 motor activity and microtubules. The structural configuration of KIF17 for ACT binding is not known, but in theory could occur in either the extended or auto-inhibited configuration. Not drawn to scale. CC, coiled-coil domains 1, 2, and 3; NC, neck coil domain.

Figure 3

Schematic diagram of diverse functions of KIF17. Radiating from KIF17 are cargos or interactions mediated by this molecular motor. Secondary extensions from the cargos and interactions signify proven or presumed functions resulting from KIF17 transport. See text for details.

Figure 4

Schematic rendition of transcriptional co-regulation by NRF-1. Not only does NRF-1 co-regulate glutamatergic neurochemicals, such as NR1/NR2B (and others not depicted here) and agents of energy metabolism, such as cytochrome c oxidase, it also regulates the motor that transports NR2B (and possibly NR1), i.e., KIF17. Membrane depolarization resulting from glutamatergic neurotransmission requires ATP generated by oxidative metabolism (of which cytochrome c oxidase is the terminal enzyme) for repolarization to enable reactivation. ATP is also used to fuel the transport motor KIF17. Thus, NRF-1 ensures that energy produced matches energy utilized in synaptic transmission by neurons. Other factors, such as CREB, may also contribute to this process, but it remains to be proven. See text for details.