Cytoplasmic dynein-1 (dynein) is an essential molecular motor controlled in part by autoinhibition. We recently identified a structure of partially autoinhibited dynein bound to Lis1, a key dynein regulator mutated in the neurodevelopmental disease lissencephaly. This structure provides an intermediate state in dynein's activation pathway; however, other structural information is needed to fully explain Lis1 function in dynein activation.
View Article and Find Full Text PDFLeucine rich repeat kinase 2 (LRRK2) is a large multidomain protein containing two catalytic domains, a kinase and a GTPase, as well as protein interactions domains, including a WD40 domain. The association of increased LRRK2 kinase activity with both the familial and sporadic forms of Parkinson's disease has led to an intense interest in determining its cellular function. However, small molecule probes that can bind to LRRK2 and report on or affect its cellular activity are needed.
View Article and Find Full Text PDFCytoplasmic dynein-1 transports intracellular cargo towards microtubule minus ends. Dynein is autoinhibited and undergoes conformational changes to form an active complex that consists of one or two dynein dimers, the dynactin complex, and activating adapter(s). The Lissencephaly 1 gene, LIS1, is genetically linked to the dynein pathway from fungi to mammals and is mutated in people with the neurodevelopmental disease lissencephaly.
View Article and Find Full Text PDFThe lissencephaly 1 gene, , is mutated in patients with the neurodevelopmental disease lissencephaly. The Lis1 protein is conserved from fungi to mammals and is a key regulator of cytoplasmic dynein-1, the major minus-end-directed microtubule motor in many eukaryotes. Lis1 is the only dynein regulator known to bind directly to dynein's motor domain, and by doing so alters dynein's mechanochemistry.
View Article and Find Full Text PDFAbscission is the terminal step of mitosis that physically separates two daughter cells [1, 2]. Abscission requires the endocytic sorting complex required for transport (ESCRT), a molecular machinery of multiple subcomplexes (ESCRT-I/II/III) that promotes membrane remodeling and scission [3-5]. Recruitment of ESCRT-I/II complexes to the midbody of telophase cells initiates ESCRT-III assembly into two rings, which subsequently expand into helices and spirals that narrow down to the incipient site of abscission [6-8].
View Article and Find Full Text PDFNeuronal function requires axon-dendrite membrane polarity, which depends on sorting of membrane traffic during entry into axons. Due to a microtubule network of mixed polarity, dendrites receive vesicles from the cell body without apparent capacity for directional sorting. We found that, during entry into dendrites, axonally destined cargos move with a retrograde bias toward the cell body, while dendritically destined cargos are biased in the anterograde direction.
View Article and Find Full Text PDFDoing scientific research can be a challenging, but creative and rewarding career. However, the challenge of doing research is orders of magnitude more difficult for scientists lacking access to the necessary resources. Resource-scarce environments are quite common worldwide and are highly contingent on the financial and social climate of one's location.
View Article and Find Full Text PDFIntracellular transport involves the regulation of microtubule motor interactions with cargo, but the underlying mechanisms are not well understood. Septins are membrane- and microtubule-binding proteins that assemble into filamentous, scaffold-like structures. Septins are implicated in microtubule-dependent transport, but their roles are unknown.
View Article and Find Full Text PDFOrganogenesis and tumor metastasis involve the transformation of epithelia to highly motile mesenchymal-like cells. Septins are filamentous G proteins, which are overexpressed in metastatic carcinomas, but their functions in epithelial motility are unknown. Here, we show that a novel network of septin filaments underlies the organization of the transverse arc and radial (dorsal) stress fibers at the leading lamella of migrating renal epithelia.
View Article and Find Full Text PDFSeptins are GTP-binding proteins that form cytoskeleton-like filaments, which are essential for many functions in eukaryotic organisms. Small molecule compounds that disrupt septin filament assembly are valuable tools for dissecting septin functions with high temporal control. To date, forchlorfenuron (FCF) is the only compound known to affect septin assembly and functions.
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