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Breaking New Cell Biology Research

Signal sequences encode information for protein folding in the endoplasmic reticulum

Sun et al. show that proteins with marginally hydrophobic signal sequences pause at the Sec61 translocon channel on their way into the ER and require Sec63/BiP to overcome the pause and facilitate subsequent protein folding in the ER. This pause-and-go mechanism prevents protein aggregation inside the ER during chaperone deficiency.

Source: Journal of Cell Biology
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  • Decoding the Cell Signals Between Young Proteins and Their ‘Chaperones’

    To aid their growth, young proteins enlist the protection of a chaperone called BiP (binding immunoglobulin protein), but how our cells make this match has remained unclear. Scientists at the Yale Nanobiology Institute have now decoded the protein signal sequences that determine the movement and timing of the protein-chaperone match – effectively revealing the blueprint for how our proteins reach maturity.

    Source: Yale West Campus
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  • Cab45 promotes lysosomal targeting of prosaposin and progranulin

    The trans-Golgi Network (TGN) sorts newly synthesized proteins to their destination via vesicular transport carriers. Despite the functional significance of packaging processes at the TGN, the sorting of soluble proteins remains enigmatic. The Golgi resident protein Cab45 is a significant regulator of secretory cargo sorting at the TGN. Cab45 oligomerizes upon transient Ca2+ influx, recruits soluble cargo molecules (clients), and packs them into vesicles. However, the identity of client molecules packed into Cab45 vesicles is scarce. Therefore, we used a highly efficient secretome analysis technology called hiSPECs. Intriguingly, we observed that Cab45 deficient cells manifest hypersecretion of lysosomal hydrolases. Specifically, Cab45 deficient cells secrete the precursors of prosaposin and progranulin. In addition, lysosomes in these cells show an aberrant perinuclear accumulation suggesting a new role of Cab45 in lysosomal positioning.

    Source: Traffic
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  • Liquid–liquid phase separation facilitates the biogenesis of secretory storage granules

    Insulin is synthesized by pancreatic β-cells and stored into secretory granules (SGs). The mechanism of how proinsulin and its processing enzymes are sorted and targeted from the trans-Golgi network (TGN) to SGs remains mysterious. No cargo receptor for proinsulin has been identified. Here, we show that chromogranin (CG) proteins undergo liquid-liquid phase separation (LLPS) at a mildly acidic pH in the lumen of the TGN, and recruit clients like proinsulin to the condensates. Client selectivity is sequence-independent but based on the concentration of the client molecules in the TGN. We propose that the TGN provides the milieu for converting CGs into a “cargo sponge,” leading to the partitioning of client molecules, thus facilitating receptor-independent client sorting. These findings provide a new receptor-independent sorting model in β-cells and many other cell types and therefore represent an innovation in the field of membrane trafficking.

    Source: Journal of Cell Biology
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  • Scientists Zero in on Genetic Causes of Parkinson’s

    In two new papers, scientists provide insight into the function of a protein called VPS13C, one of the molecular suspects that underlie Parkinson’s, a disease marked by uncontrollable movements including tremors, stiffness, and loss of balance.

    Source: YaleNews
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  • Protein and lipid trafficking in epithelial cells

    During polarization of epithelial cells, changes in the lipidome and the expression and distribution of proteins contribute to the formation of apical and basolateral plasma membrane domains. Previous studies utilizing HeLa cells showed that the Syndecan-1 transmembrane domain confers sorting within sphingomyelin-rich vesicles in a sphingomyelin secretion pathway. In polarized MDCK cells, we reveal differences in the sorting of Syndecan-1, whereupon the correct trafficking of the protein is not dependent on its transmembrane domain and changes in sphingomyelin content of cells during polarization. We show that basolateral targeting of Syndecan-1 requires a PDZ motif in Syndecan-1 and the PDZ domain Golgin protein GOPC. Moreover, we reveal changes in Golgi morphology elicited by GOPC overexpression. These results suggest the role of GOPC in sorting Syndecan-1 is indirect and likely due to GOPC effects on Golgi organization.

    Source: Molecular Biology of the Cell
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  • A group approach to growing as a principal investigator

    Laboratory researchers may not have sufficient training in the skills needed to form and manage an independent laboratory when they make the transition to Principal Investigator. A group of Yale researchers, including Valentina Greco (SWIM) addressed these challenges using principles from organizational management to navigate the groups and cultural norms of the medical school.

    Source: Current Biology
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