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Biology subjects

Gat, Y.

Publications and source records attributed to Gat, Y..

2 recordsLinked to original sources

A visual paired associate learning (vPAL) paradigm to study memory consolidation during sleep

The hippocampus helps transform an experience into an enduring memory by associating its multiple aspects. Sleep improves the consolidation of the newly formed associations, leading to stable long-term memory. Most research on human declarative memory and its consolidation during sleep uses word-pair associations requiring exhaustive learning. Here we present the visual paired association learning (vPAL) paradigm, in which participants learn new associations between images of celebrities and animals. vPAL associations are based on a one-shot exposure that resembles learning in natural conditions. We tested if vPAL can reveal a role for sleep in memory consolidation by assessing the specificity of memory recognition, and the cued recall performance, before and after sleep. We found that a daytime nap improved the stability of recognition memory and discrimination abilities compared to identical intervals of wakefulness. By contrast, cued recall of associations did not exhibit significant sleep-dependent effects. High-density EEG during naps further revealed an association between sleep spindle density and stability of recognition memory. Thus, the vPAL paradigm opens new avenues for future research on sleep and memory consolidation across ages and heterogeneous populations in health and disease.

neuroscience↗

Cryo-EM reconstructions of inhibitor-bound SMG1 kinase reveal an autoinhibitory state dependent on SMG8

The PI3K-related kinase (PIKK) SMG1 monitors progression of metazoan nonsense-mediated mRNA decay (NMD) by phosphorylating the RNA helicase UPF1. Previous work has shown that the activity of SMG1 is impaired by small molecule inhibitors, is reduced by the SMG1 interactors SMG8 and SMG9, and is downregulated by the so-called SMG1 insertion domain. However, the molecular basis for this complex regulatory network has remained elusive. Here, we present cryo-electron microscopy reconstructions of human SMG1-9 and SMG1-8-9 complexes bound to either a SMG1 inhibitor or a non-hydrolyzable ATP analogue at overall resolutions ranging from 2.8 to 3.6 [A]. These structures reveal the basis with which a small molecule inhibitor preferentially targets SMG1 over other PIKKs. By comparison with our previously reported substrate-bound structure (Langer et al. 2020), we show that the SMG1 insertion domain can exert an autoinhibitory function by directly blocking the substrate binding path as well as overall access to the SMG1 kinase active site. Together with biochemical analysis, our data indicate that SMG1 autoinhibition is stabilized by the presence of SMG8. Our results explain the specific inhibition of SMG1 by an ATP-competitive small molecule, provide insights into regulation of its kinase activity within the NMD pathway, and expand the understanding of PIKK regulatory mechanisms in general.

biochemistry↗