Segregating Bub1's mitotic functions

Release notes for dense-core vesicles V an de Bospoort et al. describe how Munc13 proteins control when and where dense-core vesicles (DCVs) are released from neurons. Neuronal DCVs contain neuropeptides and other factors that promote brain development and modulate synaptic transmission. Like neurotransmitter-containing synaptic vesicles (SVs), DCVs are released in response to action potentials and calcium infl ux, but relatively little is known about how neurons control DCV secretion. Van de Bospoort et al. designed a fluorescent probe to monitor the release of individual DCVs from hippocampal neurons in vitro. Though DCVs weren't enriched in synaptic terminals, they were preferentially secreted at synapses upon neuronal stimulation. DCV release from other parts of the neuron was less effi cient and required prolonged stimulation. To investigate why DCVs are secreted more effi ciently at synapses, Van de Bospoort et al. examined the Munc13 family of presynaptic proteins, which, by helping to assemble the SV fusion machinery, are essential for SV release. DCVs were still secreted from neurons lacking Munc13 proteins , but their release required prolonged stimulation and no longer occurred preferentially at synapses. When Munc13-1 was overex-pressed, on the other hand, it localized throughout neurons and boosted the effi ciency of extrasynaptic DCV release, such that brief stimuli induced secretion equally from synaptic and nonsynaptic sites. Therefore, although Munc13 proteins aren't required for DCV exocytosis, they facilitate secretion at synaptic termini. The researchers now want to investigate how DCVs are recruited into synapses and to determine why DCV and SV secretion are regulated differently. Opening up the ER's gatekeeper T rueman et al. describe how the Sec61 channel decides whether to open up and let proteins pass through it into the endoplasmic reticulum (ER). Proteins are directed to the ER by hydrophobic signal sequences and by cytosolic accessory factors that deliver them— either co-or posttranslationally—to Sec61 channels in the ER membrane. To permit protein translocation, Sec61's ␣ subunit undergoes a conformational change that unblocks its central pore and opens up a " lateral gate " through which signal sequences can be inserted into the channel. To understand how this conforma-tional change is triggered, Trueman et al. focused on a cluster of polar residues on either side of the lateral gate and on an adjacent patch of apolar residues in Sec61␣'s " plug domain, " which blocks the central pore when the channel is closed. Replacing these residues with polar amino acids …