Biology subjects

Jin, C. Y.

Publications and source records attributed to Jin, C. Y..

7 recordsLinked to original sources

bioRxiv2024

Separating sensory from timing processes: a cognitive encoding and neural decoding approach

The internal clock is a psychological model for timing behavior. According to information theory, psychological time might be a manifestation of information flow during sensory processing. Herein, we tested three hypotheses: (1) whether sensory adaptation reduces (or novelty increases) the rate of the internal clock (2) whether the speed of the clock reflects the amount of cortical sensory processing? (3) whether motion tunes clock speed. The current study used an oddball paradigm in which participants detected duration changes while being recorded with electroencephalography (EEG). For data analysis, we combined cognitive modeling with neural decoding techniques. Specifically, we designed Adaptive-Thought-of-Control (ACT-R) models to explain human data and linked them to the sensory EEG features discovered through machine learning. Our results indicate that timing performance is influenced by both timing and non-timing factors. The internal clock may reflect the amount of sensory processing, thereby clarifying a long-standing sensory timing mystery.

neuroscience↗

bioRxiv2023

Exploration of the Tunability of BRD4 Degradation by DCAF16 Trans-labelling Covalent Glues

Small molecules that can induce protein degradation by inducing proximity between a desired target and an E3 ligase have the potential to greatly expand the number of proteins that can be manipulated pharmacologically. Current strategies for targeted protein degradation are mostly limited in their target scope to proteins with preexisting ligands. Alternate modalities such as molecular glues, as exemplified by the glutarimide class of ligands for the CUL4CRBN ligase, have been mostly discovered serendipitously. We recently reported a trans-labelling covalent glue mechanism which we named Template-assisted covalent modification, where an electrophile decorated small molecule binder of BRD4 was effectively delivered to a cysteine residue on an E3 ligase DCAF16 as a consequence of a BRD4-DCAF16 protein-protein interaction. Herein, we report our medicinal chemistry efforts to evaluate how various electrophilic modifications to the BRD4 binder, JQ1, affect DCAF16 trans-labeling and subsequent BRD4 degradation efficiency. We discovered a decent correlation between the ability of the electrophilic small molecule to induce ternary complex formation between BRD4 and DCAF16 with its ability to induce BRD4 degradation. Moreover, we show that a more solvent-exposed warhead presentation is optimal for DCAF16 recruitment and subsequent BRD4 degradation. Unlike the sensitivity of CUL4CRBN glue degraders to chemical modifications, the diversity of covalent attachments in this class of BRD4 glue degraders suggests a high tolerance and tunability for the BRD4-DCAF16 interaction. This offers a potential new avenue for a rational design of covalent glue degraders by introducing covalent warheads to known binders.

pharmacology and toxicology↗

bioRxiv2023

Template-assisted covalent modification of DCAF16 underlies activity of BRD4 molecular glue degraders

Small molecules that induce protein-protein interactions to exert proximity-driven pharmacology such as targeted protein degradation are a powerful class of therapeutics1-3. Molecular glues are of particular interest given their favorable size and chemical properties and represent the only clinically approved degrader drugs4-6. The discovery and development of molecular glues for novel targets, however, remains challenging. Covalent strategies could in principle facilitate molecular glue discovery by stabilizing the neo-protein interfaces. Here, we present structural and mechanistic studies that define a trans-labeling covalent molecular glue mechanism, which we term "template-assisted covalent modification". We found that a novel series of BRD4 molecular glue degraders act by recruiting the CUL4DCAF16 ligase to the second bromodomain of BRD4 (BRD4BD2). BRD4BD2, in complex with DCAF16, serves as a structural template to facilitate covalent modification of DCAF16, which stabilizes the BRD4-degrader-DCAF16 ternary complex formation and facilitates BRD4 degradation. A 2.2 [A] cryo-electron microscopy structure of the ternary complex demonstrates that DCAF16 and BRD4BD2 have pre-existing structural complementarity which optimally orients the reactive moiety of the degrader for DCAF16Cys58 covalent modification. Systematic mutagenesis of both DCAF16 and BRD4BD2 revealed that the loop conformation around BRD4His437, rather than specific side chains, is critical for stable interaction with DCAF16 and BD2 selectivity. Together our work establishes "template-assisted covalent modification" as a mechanism for covalent molecular glues, which opens a new path to proximity driven pharmacology.

biochemistry↗

bioRxiv2023

HAPSTR1 localizes HUWE1 to the nucleus to limit stress signaling pathways

HUWE1 is a large, enigmatic HECT domain ubiquitin ligase implicated in the regulation of diverse pathways including DNA repair, apoptosis, and differentiation. How HUWE1 engages its structurally diverse substrates and how HUWE1 activity is regulated are unknown. Using unbiased quantitative proteomics, we identify C16orf72/HAPSTR1 as a dedicated HUWE1 substrate despite HUWE1 targeting substrates in a largely cell type-specific manner. The established physical and genetic interactions between HUWE1 and C16orf72/HAPSTR1 suggest that HAPSTR1 positively regulates HUWE1 function. Here, we show that HAPSTR1 is both a HUWE1 substrate and is required for HUWE1 nuclear localization to facilitate HUWE1 nuclear substrate targeting. HUWE1 or HAPSTR1 loss of function triggers a broad transcriptional stress response. We show that nuclear HUWE1 is both critical for modulating stress signaling pathways, which include p53 and NF-{kappa}B-mediated signaling and required for cell proliferation. Combined, our results define a role for HAPSTR1 in gating critical nuclear HUWE1 functions.

molecular biology↗

bioRxiv2022

Structures of BIRC6-Client Complexes Provide Mechanism of Smac-Mediated Release of Caspases

Apoptosis is tightly regulated and essential for metazoan development1, 2. Excessive apoptosis contributes to neurodegenerative disease, while diminished apoptosis can lead to inflammation and cancer3. Inhibitor of apoptosis (IAP) proteins are the principal actors that restrain apoptotic activity and are thus attractive therapeutic targets4. IAPs in turn are regulated by mitochondria-derived pro-apoptotic factors such as Smac and HtrA24. Here, through a series of cryo-electron microscopy (cryo-EM) structures of full-length baculoviral IAP repeat-containing protein 6 (BIRC6) bound to Smac, caspase-3, caspase-7 and HtrA2, we provide the molecular basis for BIRC6-mediated caspase inhibition and its release by Smac. We demonstrate that BIRC6 cooperates preferentially with the non-canonical E1 enzyme UBA6 to ubiquitylate caspases and that caspase ubiquitylation is effectively inhibited by Smac through near-irreversible interactions. The dimeric arrangement of BIRC6 resolves the long-standing question of how the evolutionarily conserved single-BIR domain IAPs sequester caspases and how Smac binding antagonizes IAPs. This collection of BIRC6 structures provides critical insights into IAP-mediated apoptosis regulation, relevant for the development of current and future apoptosis-targeting cancer therapeutics.

molecular biology↗

bioRxiv2020

Decoding Study-Independent Mind-Wandering from EEG using Convolutional Neural Networks

ObjectiveMind-wandering is a mental phenomenon where the internal thought process disengages from the external environment periodically. In the current study, we trained EEG classifiers using convolutional neural networks (CNN) to track mind-wandering across studies. ApproachWe transformed the input from raw EEG to band-frequency information (power), singletrial ERP (stERP) patterns, and connectivity matrices between channels (based on inter-site phase clustering, ISPC). We trained CNN models for each input type from each EEG channel as the input model for the meta-learner. To verify the generalizability, we used leave-N-participant-out crossvalidations (N=6) and tested the meta-learner on the data from an independent study for across-study predictions. Main resultsThe current results show limited generalizability across participants and tasks. Nevertheless, our meta-learned trained with the stERPs performed the best among the state-of-theart neural networks. The mapping of each input model to the output of the meta-learner indicates the importance of each EEG channel. SignificanceOur study makes the first attempt to train study-independent mind-wandering classifiers. The results indicate that this remains challenging. The current proposed stacking neural network design allows an easy inspection of channel importance and feature maps.

neuroscience↗

bioRxiv2020

Modular HUWE1 architecture serves as hub for degradation of cell-fate decision factors

HECT ubiquitin ligases play essential roles in metazoan development and physiology. The HECT ligase HUWE1 is central to the cellular stress response by mediating degradation of key death or survival factors including Mcl1, p53, DDIT4, and Myc. As a step toward understanding regulation of HUWE1 engagement with its diverse substrates, we present here the cryo-EM structure of HUWE1, offering a first complete molecular picture of a HECT ubiquitin ligase. The ~4400 amino acid residue polypeptide forms an alpha solenoid-shaped assembly with a central pore decorated with protein interaction modules. This modularity enables HUWE1 to target a wide range of substrates for destruction. The locations of human mutations associated with severe neurodevelopmental disorders link functions of this essential enzyme with its three-dimensional organization.

molecular biology↗