Normal cellular function requires that organelles be positioned in specific locations. The direction in which molecular motors move organelles is based in part on the polarity of microtubules and actin filaments. However, this alone does not determine the intracellular destination of organelles. For example, the yeast class V myosin, Myo2p, moves several organelles to distinct locations during the cell cycle. Thus the movement of each type of Myo2p cargo must be regulated uniquely. Here we report a regulatory mechanism that specifically provides directionality to vacuole movement. The vacuole-specific Myo2p receptor, Vac17p, has a key function in this process. Vac17p binds simultaneously to Myo2p and to Vac8p, a vacuolar membrane protein. The transport complex, Myo2p-Vac17p-Vac8p, moves the vacuole to the bud, and is then disrupted through the degradation of Vac17p. The vacuole is ultimately deposited near the centre of the bud. Removal of a PEST sequence (a potential signal for rapid protein degradation) within Vac17p causes its stabilization and the subsequent 'backward' movement of vacuoles, which mis-targets them to the neck between the mother cell and the bud. Thus the regulated disruption of this transport complex places the vacuole in its proper location. This may be a general mechanism whereby organelles are deposited at their terminal destination.
Class V myosins are widely distributed among diverse organisms and move cargo along actin filaments. Some myosin Vs move multiple types of cargo, where the timing of movement and the destinations of selected cargoes are unique. Here, we report the discovery of an organelle-specific myosin V receptor. Vac17p, a novel protein, is a component of the vacuole-specific receptor for Myo2p, a Saccharomyces cerevisiae myosin V. Vac17p interacts with the Myo2p cargo-binding domain, but not with vacuole inheritance-defective myo2 mutants that have single amino acid changes within this region. Moreover, a region of the Myo2p tail required specifically for secretory vesicle transport is neither required for vacuole inheritance nor for Vac17p–Myo2p interactions. Vac17p is localized on the vacuole membrane, and vacuole-associated Myo2p increases in proportion with an increase in Vac17p. Furthermore, Vac17p is not required for movement of other cargo moved by Myo2p. These findings demonstrate that Vac17p is a component of a vacuole-specific receptor for Myo2p. Organelle-specific receptors such as Vac17p provide a mechanism whereby a single type of myosin V can move diverse cargoes to distinct destinations at different times.
BackgroundSudden unexpected death in epilepsy (SUDEP) is a major cause of death in those with drug-resistant epilepsy (DRE). There is a need for inventories and biomarkers associated with the risk for SUDEP.ObjectiveTo explore the revised SUDEP Risk Inventory (SUDEP-7) in a cohort with DRE and determine the association with Heart Rate and other covariates.MethodsTwenty-five subjects with severe DRE were enrolled in a clinical trial for epilepsy. Baseline demographics, duration of epilepsy, seizure types, seizure frequency, seizure severity, AEDs, and vital signs were collected. Heart rate variability (HRV) was calculated from 1-h recordings of ECG. A SUDEP Risk Inventory (SUDEP-7) was administered, which included seven validated and weighted risk factors initially identified by Walczak et al. as factors associated with SUDEP risk.ResultsThe total score on the revised SUDEP-7 ranged from 1 to 7, mean = 3.4 (SD 1.8). The SUDEP Risk Inventory score was inversely correlated with RMSSD (Pearson r = −0.45, p = 0.027). The following variables were significantly associated with RMSSD: epilepsy duration (p = 0.02), age (p = 0.03), and developmental intellectual disability (p < 0.001). The correlation between RMSSD and SUDEP-7 tended to persist also after the adjustment for patient age (r = −0.40, p = 0.05). Two subjects died of SUDEP: their SUDEP-7 scores were above average and in the upper twenty-fifth and fiftieth percentiles, respectively (6 and 4, mean = 3.4).ConclusionRMSSD, a measure of low frequency HRV, was significantly associated with SUDEP Risk Inventory (SUDEP-7) scores. Using a multivariate model, the covariates of developmental intellectual disability, age, and duration of epilepsy were also significantly associated with decreased HRV. The correlation between decreased HRV and a higher SUDEP-7 score remained unchanged even after the adjustment for patient age. The results suggest that older age, greater duration of epilepsy, and the presence of developmental intellectual disability may increase the risk of SUDEP through their direct influence on decreasing the vagus nerve-mediated HRV. Further validation of the SUDEP-7 inventory is indicated.Trial RegistrationClinicalTrials.gov, NCT00871377.
The myosin V carboxyl-terminal globular tail domain is essential for the attachment of myosin V to all known cargoes. Previously, the globular tail was viewed as a single, functional entity. Here, we show that the globular tail of the yeast myosin Va homologue, Myo2p, contains two structural subdomains that have distinct functions, namely, vacuole-specific and secretory vesicle–specific movement. Biochemical and genetic analyses demonstrate that subdomain I tightly associates with subdomain II, and that the interaction does not require additional proteins. Importantly, although neither subdomain alone is functional, simultaneous expression of the separate subdomains produces a functional complex in vivo. Our results suggest a model whereby intramolecular interactions between the globular tail subdomains help to coordinate the transport of multiple distinct cargoes by myosin V.
Most amyotrophic lateral sclerosis (ALS) cases are considered sporadic, without a known genetic basis, and environmental exposures are thought to play a causal role. To learn more about sporadic ALS etiology, we recruited n = 188 ALS patients from northern New England and Ohio and matched controls 2:1 from the general population of the same regions. Questionnaires evaluated the association between a variety of lifestyle, behavioral (ie, hobbies and activities), and occupational factors and the risk of ALS, including the duration of time between exposure and ALS onset, and exposure frequency. Head trauma was associated with increased ALS risk
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