The Structure of ApoB100 from Human Low-density Lipoprotein

Berndsen, Zachary T.; Cassidy, C. Keith

doi:10.1101/2024.02.28.582555

Cited by 2 publications

(1 citation statement)

References 101 publications

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“…Lipoproteins in mammals arise from the ER containing a neutral lipid core delimited by a monolayer of phospholipids 4,38 . During their synthesis, apolipoproteins such as ApoB associate with their surface [39][40][41] . In contrast, C. elegans vitellogenin has been observed within membrane bound vesicles during their transit to stations of the secretory pathway 42 .…”

Section: Discussionmentioning

confidence: 99%

A distant TANGO1 family member promotes vitellogenin export from the ER inC. elegans

Mo,

Zhai,

Jung

et al. 2024

Preprint

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SummaryVitellogenin belongs to the Large Lipid Transfer Protein superfamily and is thought to share a common ancestor with human Apolipoprotein B (ApoB) for systemic lipid transport1–5. Vitellogenin forms part of yolk granules (also known as yolk organelles), as maternal contribution of nutrients that support the embryonic development of oviparous animals6,7. InCaenorhabditis elegans, vitellogenin proteins (VIT-1 to VIT-6) are synthesized in the hermaphrodite intestine, secreted into the pseudocoelom and internalized by oocytes8–13. Although a general route for inter-tissue vitellogenin transport has been described, the full mechanism that underlies its intracellular trafficking within the intestine remains obscure9,12,13. In humans, transport and Golgi organization protein 1 (TANGO1) and TANGO1-like (TALI) proteins generate super-sized membrane carriers to accommodate bulky ApoB-containing lipoprotein particles for their export from ER exit sites14–17. Transport facilitated by TANGO1 family of proteins is considered as an alternative, COPII-independent ER exit pathway18–24. Thus far, TANGO1 orthologs have been discovered in most metazoans, except nematodes24,25. Here, we report theC. elegansprotein R148.3 (nowTransport andGolgi organization 1-like or TNGL-1) as a mediator of vitellogenin export from the ER. TNGL-1 depletion triggers VIT-2 accumulation in the intestinal ER lumen. TNGL-1 requires its C-terminal unstructured domain for its localization to ER exit sites. Like TANGO1, it utilizes a luminal globular domain for cargo engagement. Our findings support TNGL-1 as a distant TANGO1 family member.

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Section: Discussionmentioning

confidence: 99%

A distant TANGO1 family member promotes vitellogenin export from the ER inC. elegans

Mo,

Zhai,

Jung

et al. 2024

Preprint

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Proteomic evidence for amyloidogenic cross-seeding in fibrinaloid microclots

Kell,

Pretorius

2024

Preprint

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In classical amyloidoses, amyloid fibres form through the nucleation and accretion of protein monomers, with protofibrils and fibrils exhibiting a cross-β motif of parallel or antiparallel β-sheets oriented perpendicular to the fibre direction. These protofibrils and fibrils can intertwine to form mature amyloid fibres. Similar phenomena occur in blood from individuals with circulating inflammatory molecules (also those originating from viruses and bacteria). In the presence of inflammagens, pathological clotting can occur, that results in an anomalous amyloid form termed fibrinaloid microclots. Previous proteomic analyses of these microclots have shown the presence of non-fibrin(ogen) proteins, suggesting a more complex mechanism than simple entrapment. We provide evidence against a simple entrapment model, noting that clot pores are too large and centrifugation would have removed weakly bound proteins. Instead, we explore whether co-aggregation into amyloid fibres may involve axial (multiple proteins within the same fibril), lateral (single-protein fibrils contributing to a fibre), or both types of integration. Our analysis of proteomic data from fibrinaloid microclots in different diseases shows no significant overlap with the normal plasma proteome and no correlation between plasma protein abundance and presence in microclots. Notably, abundant plasma proteins like α-2-macroglobulin, fibronectin, and transthyretin are absent from microclots, while less abundant proteins such as adiponectin, periostin, and von Willebrand Factor are well represented. Using bioinformatic tools including AmyloGram and AnuPP, we found that proteins entrapped in fibrinaloid microclots exhibit high amyloidogenic tendencies, suggesting their integration as cross-β elements into amyloid structures. This integration likely contributes to the microclots’ resistance to proteolysis. Our findings underscore the role of cross-seeding in fibrinaloid microclot formation and highlight the need for further investigation into their structural properties and implications in thrombotic and amyloid diseases. These insights provide a foundation for developing novel diagnostic and therapeutic strategies targeting amyloidogenic cross-seeding in blood clotting disorders.

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The Structure of ApoB100 from Human Low-density Lipoprotein

Cited by 2 publications

References 101 publications

A distant TANGO1 family member promotes vitellogenin export from the ER inC. elegans

A distant TANGO1 family member promotes vitellogenin export from the ER inC. elegans

Proteomic evidence for amyloidogenic cross-seeding in fibrinaloid microclots

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