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Salogiannis, J.

Publications and source records attributed to Salogiannis, J..

2 recordsLinked to original sources

Regulation of peroxisome and lipid droplet hitchhiking by PxdA and the DipA phosphatase

In canonical microtubule-based transport, adaptor proteins link cargos to the molecular motors dynein and kinesin. Recently, an alternative mode of transport known as hitchhiking was discovered, in which a cargo achieves motility by hitching a ride on an already-motile cargo, rather than attaching to a motor protein. Hitchhiking has been best-studied in two filamentous fungi, Aspergillus nidulans and Ustilago maydis. In U. maydis, ribonucleoprotein complexes, peroxisomes, lipid droplets, and endoplasmic reticulum all hitchhike on early endosomes. In A. nidulans, peroxisomes hitchhike using a putative molecular linker, PxdA, that associates with early endosomes. However, whether other organelles use PxdA to hitchhike on early endosomes is unclear, as are the molecular mechanisms that regulate hitchhiking in A. nidulans. Here we find that the proper distribution of lipid droplets, mitochondria and autophagosomes do not require PxdA, suggesting that PxdA is a molecular linker specific to peroxisomes. We also identify two new pxdA alleles, including a point mutation (R2044P) that disrupts PxdAs ability to associate with early endosomes and reduces peroxisome movement. Finally, we identify a novel regulator of peroxisome hitchhiking, the phosphatase DipA. DipA co-localizes with early endosomes and its early endosome-association relies on PxdA.

cell biology

Parkinson's Disease-linked LRRK2 structure and model for microtubule interaction

Leucine Rich Repeat Kinase 2 (LRRK2) is the most commonly mutated gene in familial Parkinsons disease. LRRK2 is proposed to function in membrane trafficking and co-localizes with microtubules. We report the 3.5[A] structure of the catalytic half of LRRK2, and an atomic model of microtubule-associated LRRK2 built using a reported 14[A] cryo-electron tomography in situ structure. We propose that the conformation of LRRK2s kinase domain regulates its microtubule interaction, with a closed conformation favoring binding. We show that the catalytic half of LRRK2 is sufficient for microtubule binding and blocks the motility of the microtubule-based motors kinesin and dynein in vitro. Kinase inhibitors that stabilize an open conformation relieve this interference and reduce LRRK2 filament formation in cells, while those that stabilize a closed conformation do not. Our findings suggest that LRRK2 is a roadblock for microtubule-based motors and have implications for the design of therapeutic LRRK2 kinase inhibitors.

biophysics