期刊
JOURNAL OF CELL SCIENCE
卷 130, 期 9, 页码 1637-1651出版社
COMPANY OF BIOLOGISTS LTD
DOI: 10.1242/jcs.198267
关键词
Kinesin-1; SKIP; Lysosome positioning; Microtubule transport
类别
资金
- Biotechnology and Biological Sciences Research Council (BBSRC) [BB/L006774/1]
- Wellcome Trust Research Career Development Fellowship [097316/Z/11/Z]
- Wellcome Trust [097316/Z/11/Z] Funding Source: Wellcome Trust
- BBSRC [BB/L006774/1] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [BB/L006774/1] Funding Source: researchfish
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 tryptophanacidic- 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.
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