The Effector Domain of Human Dlg Tumor Suppressor Acts as a Switch That Relieves Autoinhibition of Kinesin-3 Motor GAKIN/KIF13B †
| Autor: | Athar H. Chishti, Toshihiko Hanada, Kaori H. Yamada |
|---|---|
| Rok vydání: | 2023 |
| Předmět: |
Scaffold protein
Models Molecular Guanylate kinase Recombinant Fusion Proteins Molecular Sequence Data Kinesins Biology Biochemistry Synaptic vesicle Models Biological Article Discs Large Homolog 1 Protein Enzyme Reactivators Microtubule Cell polarity Animals Humans KIF1A Adaptor Proteins Signal Transducing Uncategorized Adenosine Triphosphatases Molecular Motor Proteins Membrane Proteins Transport protein Cell biology Protein Structure Tertiary Protein Transport Kinesin Carrier Proteins Microtubule-Associated Proteins Protein Binding |
| DOI: | 10.25417/uic.21235710 |
| Popis: | Kinesin motors mediate the intracellular transport of cargo molecules along microtubule tracks (1). The mechanism that regulates the activation of kinesin motors remains an issue of fundamental importance (2, 3). It has been reported that the full length conventional kinesin, kinesin-1, has very little microtubule-stimulated ATPase activity in solution as compared to its shorter motor domain constructs (4, 5). The intramolecular interactions mediated by the motor and tail domains keep the kinesin-1 in a compactly-folded inhibitory state (6–8). It is well established that the mechanical attachment of the inactive full length motor to a glass surface or latex beads is sufficient to transform the inactive motor to an active state, presumably by disrupting its inhibitory conformation (8, 9). Therefore, it is reasonable to speculate that this mode of self-inhibition of kinesin-1 is the general feature conserved in all kinesin-like proteins to keep their motor activity regulated in vivo. GAKIN/KIF13B (10) belongs to the kinesin-3 family. The family also includes KIF1A/Unc104, which is responsible for the transport of synaptic vesicles (11). Our previous studies have identified two cargo molecules for GAKIN; the membrane-associated guanylate kinase homologue (MAGUK) scaffolding protein hDlg/SAP97 (12) and a PIP3 binding protein termed PIP3BP (13). Both MAGUKs and PIP3 have been implicated in the regulation of cell polarity pathways, and their subcellular localization is considered to be important for their functions in vivo. Recently, we have shown that the transport of PIP3 containing vesicles to the distal ends of neurites by the GAKIN-PIP3BP complex regulates the axon-dendrite polarity determination in the hippocampal neurons (13). Human Dlg is an important component of cell-cell contact sites such as epithelial adherence junctions and neuronal synaptic membranes, where it forms a multi-protein complex containing transmembrane receptors and cytoskeletal proteins (14). The loss of Drosophila Dlg disrupts epithelial apical-basal polarity resulting in the tumor-like overgrowth in imaginal discs (15). MAGUK proteins are also implicated in the transport of multi-protein complexes to specialized sites. For example, SAP97, the rat orthologue of hDlg, regulates the transport of AMPA receptor complex to the synapse (16–18). A scaffolding complex containing Lin-2, another MAGUK, mediates the transport of the NMDA receptor (19). These findings prompted us to investigate the regulatory mechanism of the hDlg-GAKIN cargo-motor complex and its role in the transport phenomenon. Here, we report that a specific segment of hDlg encodes the activation signal for converting an inactive GAKIN to an active motor in vitro. To our knowledge, this is the first demonstration of the regulation of a kinesin motor by direct interaction of its natural cargo using in vitro measurements of purified components. |
| Databáze: | OpenAIRE |
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