Catálogo de publicaciones - revistas

<jats:p>Inhibitor of apoptosis proteins (IAPs) bind to pro-apoptotic proteases, keeping them inactive and preventing cell death. The atypical ubiquitin ligase BIRC6 is the only essential IAP, additionally functioning as a suppressor of autophagy. We performed a structure-function analysis of BIRC6 in complex with caspase-9, HTRA2, SMAC, and LC3B which are critical apoptosis and autophagy proteins. Cryo-electron microscopy structures show that BIRC6 forms a megadalton crescent shape that arcs around a spacious cavity containing receptor sites for client proteins. Multivalent binding of SMAC obstructs client binding, impeding ubiquitination of both autophagy and apoptotic substrates. Based on these data, we discuss how the BIRC6/SMAC complex can act as a stress-induced hub to regulate apoptosis and autophagy drivers.</jats:p>

<jats:p>Certain Inhibitors of apoptosis (IAP) family members are sentinel proteins preventing untimely cell death by inhibiting caspases. Antagonists including second mitochondria-derived activator of caspase (SMAC) regulate IAPs, driving cell death. Baculoviral IAP repeat-containing protein 6 (BIRC6), a giant IAP with dual E2/E3 ubiquitin ligase activity, regulates programmed cell death through unknown mechanisms. We show BIRC6 directly restricts executioner caspases-3 and -7, and ubiquitinates caspases-3, -7 and -9 working exclusively with non-canonical E1, UBA6. Importantly, we show SMAC suppresses both mechanisms. Cryo-electron microscopy structures of BIRC6 alone and in complex with SMAC reveals BIRC6 is an anti-parallel dimer juxtaposing the substrate-binding module against the catalytic domain. Furthermore, we discover SMAC multi-site binding to BIRC6 results in a sub-nanomolar affinity interaction, enabling SMAC to competitively displace caspases thus antagonizing BIRC6 anti-caspase function.</jats:p>

<jats:p>Tight regulation of apoptosis is essential for metazoan development and prevents diseases such as cancer and neurodegeneration. Caspase activation is central to apoptosis and inhibitor of apoptosis (IAP) proteins are the principal actors that restrain caspase activity and are therefore attractive therapeutic targets. IAPs, in turn, are regulated by mitochondria-derived pro-apoptotic factors such as Smac and HtrA2. Through a series of cryo-electron microscopy (cryo-EM) structures of full-length human baculoviral IAP repeat-containing protein 6 (BIRC6) bound to Smac, caspases, and HtrA2, we provide a molecular understanding for BIRC6-mediated caspase inhibition and its release by Smac. The architecture of BIRC6, together with near-irreversible binding of Smac, elucidates how the IAP inhibitor Smac can effectively control a processive ubiquitin ligase to respond to apoptotic stimuli.</jats:p>

<jats:p> Transient sexual experiences can have long-lasting effects on behavioral decisions, but the neural coding that accounts for this change is unclear. We found that ejaculation experience selectively activated estrogen receptor 2 ( <jats:italic>Esr2</jats:italic> )-expressing neurons in the bed nucleus of the stria terminalis (BNST)—BNST <jats:sup>Esr2</jats:sup> —and led to persistent decreases in firing threshold for days, during which time the mice displayed sexual satiety. Inhibition of hyperexcited BNST <jats:sup>Esr2</jats:sup> elicited fast mating recovery in satiated mice of both sexes. In males, such hyperexcitability reduced mating motivation and was partially mediated by larger HCN currents. Thus BNST <jats:sup>Esr2</jats:sup> not only encode a specific mating action but also represent a persistent state of sexual satiety, and alterations in a neuronal ion channel contribute to sexual experience–dependent long-term changes to mating drive. </jats:p>

<jats:p> Wang <jats:italic>et al</jats:italic> . (Research Articles, 3 June 2022, eabl8316) reported an early Miocene giraffoid that exhibited fierce head-butting behavior and concluded that sexual selection promoted head-neck evolution in giraffoids. However, we argue that this ruminant is not a giraffoid and thus that the hypothesis that sexual selection promoted giraffoid head-neck evolution is not sufficiently supported. </jats:p>

<jats:p> Hou <jats:italic>et al</jats:italic> . challenged the giraffoid affinity of <jats:italic>Discokeryx</jats:italic> and its ecology and behavior. In our response we reiterate that <jats:italic>Discokeryx</jats:italic> is a giraffoid that, along with <jats:italic>Giraffa</jats:italic> , shows extreme evolution of head-neck morphologies that were presumably shaped by selective pressure from sexual competition and marginal environments. </jats:p>

<jats:p>Social media giant wants to monetize its global data set</jats:p>

<jats:p>Campaign seeks to understand reflective particles in the stratosphere, which planet-cooling schemes would enhance</jats:p>

<jats:p>Psychedelics act on intracellular serotonin receptors that are not accessible by serotonin alone</jats:p>