SKIP controls lysosome positioning using a composite kinesin-1 heavy and light chain-binding domain
| Autor: | Sanger, Anneri, Yip, Yan Y., Randall, Thomas S., Pernigo, Stefano, Steiner, Roberto A., Dodding, Mark P. |
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| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
Microtubule transport
Binding Sites Amino Acid Motifs Calcium-Binding Proteins kinesin-1 Kinesins macromolecular substances Rats SKIP Lysosome positioning Protein Domains Mutation Kinesin-1 Animals Humans Amino Acid Sequence Lysosomes Research Article Adaptor Proteins Signal Transducing HeLa Cells Protein Binding |
| Zdroj: | Journal of Cell Science Sanger, A, Yip, Y Y, Randall, T S, Pernigo, S, Steiner, R A & Dodding, M P 2017, ' SKIP controls lysosome positioning using a composite kinesin-1 heavy and light chain-binding domain ', Journal of Cell Science, vol. 130, no. 9, pp. 1637-1651 . https://doi.org/10.1242/jcs.198267 Sanger, A, Yip, Y Y, Randall, T S, Pernigo, S, Steiner, R A & Dodding, M P 2017, ' SKIP controls lysosome positioning using a composite kinesin-1 heavy and light chain binding domain ', Journal of cell science, vol. 130, no. 9, pp. 1637-1651 . https://doi.org/10.1242/jcs.198267 |
| DOI: | 10.1242/jcs.198267 |
| Popis: | The molecular interplay between cargo recognition and regulation of the activity of the kinesin-1 microtubule motor is not well understood. Using the lysosome adaptor SKIP (also known as PLEKHM2) as model cargo, we show that the kinesin heavy chains (KHCs), in addition to the kinesin light chains (KLCs), can recognize tryptophan-acidic-binding determinants on the cargo when presented in the context of an extended KHC-interacting domain. Mutational separation of KHC and KLC binding shows that both interactions are important for SKIP–kinesin-1 interaction in vitro and that KHC binding is important for lysosome transport in vivo. However, in the absence of KLCs, SKIP can only bind to KHC when autoinhibition is relieved, suggesting that the KLCs gate access to the KHCs. We propose a model whereby tryptophan-acidic cargo is first recognized by KLCs, resulting in destabilization of KHC autoinhibition. This primary event then makes accessible a second SKIP-binding site on the KHC C-terminal tail that is adjacent to the autoinhibitory IAK region. Thus, cargo recognition and concurrent activation of kinesin-1 proceed in hierarchical stepwise fashion driven by a dynamic network of inter- and intra-molecular interactions. Summary: The lysosomal kinesin-1 cargo adaptor SKIP is shown to interact with kinesin-1 via both its heavy and light chains. A new stepwise hierarchical model for kinesin-1 activation is proposed. |
| Databáze: | OpenAIRE |
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