Abstract
The kinesin-3 KIF1C is a fast organelle transporter implicated in the transport of dense core vesicles in neurons and the delivery of integrins to cell adhesions. Here we report the mechanisms of autoinhibition and release that control the activity of KIF1C. We show that the microtubule binding surface of KIF1C motor domain interacts with its stalk and that these autoinhibitory interactions are released upon binding of protein tyrosine phosphatase PTPN21. The FERM domain of PTPN21 stimulates dense core vesicle transport in primary hippocampal neurons and rescues integrin trafficking in KIF1C-depleted cells. In vitro, human full-length KIF1C is a processive, plus-end directed motor. Its landing rate onto microtubules increases in the presence of either PTPN21 FERM domain or the cargo adapter Hook3 that binds the same region of KIF1C tail. This autoinhibition release mechanism allows cargo-activated transport and might enable motors to participate in bidirectional cargo transport without undertaking a tug-of-war.
Highlights
The kinesin-3 KIF1C is a fast organelle transporter implicated in the transport of dense core vesicles in neurons and the delivery of integrins to cell adhesions
We find that the apparent molecular weight determined both at physiological levels of salt (150 mM) and in high (500 mM) salt buffer is consistent with KIF1C being a dimer
Consistent with the idea that the stalk competes with microtubule binding, we found that microtubule decoration by the KIF1C motor domain was significantly reduced in the presence of 1 μM stalk domain, but not when 1 μM GST was added as control (Fig. 2g, h)
Summary
The kinesin-3 KIF1C is a fast organelle transporter implicated in the transport of dense core vesicles in neurons and the delivery of integrins to cell adhesions. Its landing rate onto microtubules increases in the presence of either PTPN21 FERM domain or the cargo adapter Hook[3] that binds the same region of KIF1C tail. This autoinhibition release mechanism allows cargoactivated transport and might enable motors to participate in bidirectional cargo transport without undertaking a tug-of-war. We demonstrate that protein tyrosine phosphatase N21 (PTPN21) activates KIF1C by binding to the stalk region This function does not require catalytic activity of the phosphatase, and its N-terminal FERM domain alone is sufficient to stimulate the transport of KIF1C cargoes in cells as well as increasing the landing rate of KIF1C on microtubules in vitro. The cargo adapter Hook[3] binds KIF1C in the same region and activates KIF1C in a similar way, suggesting that both cargo binding and regulatory proteins might contribute to the directional switching of KIF1C–dynein transport complexes
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