The α-Helical Structure of Prodomains Promotes Translocation of Intrinsically Disordered Neuropeptide Hormones into the Endoplasmic Reticulum

Dirndorfer, Daniela; Seidel, R.; Nimrod, Guy; Miesbauer, Margit; Ben‐Tal, Nir; Engelhard, Martin; Zimmermann, Richard; Winklhofer, Konstanze F.; Tatzelt, Jörg

doi:10.1074/jbc.m112.430264

Cited by 15 publications

(25 citation statements)

References 73 publications

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“…Proglucagon is a unique prohormone from the perspective of its structural organization. Several prohormones, such as pro-thyrotropin-releasing hormone and pro-gonadotropin-releasing hormone, have structured prodomains, whereas the active hormone domain(s) are completely disordered (31). In contrast, proglucagon exhibits disordered prodomains (GRPP, IP-1, and IP-2), with mostly ordered hormone domains, as our previous work has shown (33).…”

Section: Discussionmentioning

confidence: 86%

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Two Dipolar α-Helices within Hormone-encoding Regions of Proglucagon Are Sorting Signals to the Regulated Secretory Pathway

Guizzetti¹,

McGirr

Dhanvantari

2014

Journal of Biological Chemistry

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Background:The constituent peptides of proglucagon contain ␣-helices that may target proglucagon to secretory granules. Results: Sorting of proglucagon processing intermediates is context-dependent, despite containing two sorted domains of glucagon and glucagon-like peptide 1. Conclusion: Proglucagon sorting is directed by two dipolar ␣-helices within glucagon and GLP-1. Significance: Hormone domains, rather than disordered prodomains, encode proglucagon sorting signals.

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Section: Discussionmentioning

confidence: 86%

“…Interestingly, unlike other prohormones, the ␣-helices lie within ordered hormone-encoding regions and not in a prodomain (31). Additionally, these hormone domains are evolutionarily conserved, particularly regarding their biophysical characteristics (32).…”

mentioning

confidence: 99%

Two Dipolar α-Helices within Hormone-encoding Regions of Proglucagon Are Sorting Signals to the Regulated Secretory Pathway

Guizzetti¹,

McGirr

Dhanvantari

2014

Journal of Biological Chemistry

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“…Different from CPP, it delivers peptides to the cell membrane, but does not accompany them into the cytosol (Figure 1f), thus avoiding any intracellular influence of the material on the target cells. More interestingly, PEG-PE micelles can transform peptides from non-α-helix into α-helix, which is favorable for membrane translocation [46]. In fact, several endeavors have been made to stabilize peptides in α-helix for better cytosolic delivery [12–16].…”

Section: Discussionmentioning

confidence: 99%

Coordinating antigen cytosolic delivery and danger signaling to program potent cross-priming by micelle-based nanovaccine

et al. 2017

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Although re-activating cytotoxic T-cell (CTLs) response inside tumor tissues by checkpoint blockade has demonstrated great success in tumor immunotherapy, active induction of efficient endogenous CTL response by therapeutic vaccines has been largely hampered by inefficient cytosolic delivery of antigens and coordinated activation of dendritic cells (DCs) in lymph nodes. Here we show that polyethylene glycol-phosphatidylethanolamine (PEG-PE) micelles transform soluble peptides into α-helix to enable their efficient cytosolic delivery. The same PEG-PE micelles also serve as chaperon of TLR4 signaling to coordinate its adjuvant effect on the same DCs. Furthermore, these nanovaccines effectively target lymph node DCs. Thus, PEG-PE micelle vaccines program at multiple key aspects for inducing strong CTL responses and build up a foundation for combinational tumor therapy.

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“…Employing neuropeptide hormones and model substrates we could then show that impaired ER import of intrinsically disordered proteins (IDPs) is a general phenomenon and not a specific feature of PrP mutants. Specifically, these studies revealed that IDPs require alpha-helical domains in addition to the N-terminal signal peptide for efficient Sec61-mediated transport into the ER [16,[18][19][20][21].…”

Section: Prion Protein-induced Neurodegenerationthe Cytoplasmic Connementioning

confidence: 99%

Impaired transport of intrinsically disordered proteins through the Sec61 and SecY translocon; implications for prion diseases

Jung

Tatzelt

2018

Prion

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The prion protein (PrP) is composed of two major domains of similar size. The structured C-terminal domain contains three alpha-helical regions and a short two-stranded beta-sheet, while the N-terminal domain is intrinsically disordered. The analysis of PrP mutants with deletions in the C-terminal globular domain provided the first hint that intrinsically disordered domains are inefficiently transported into the endoplasmic reticulum through the Sec61 translocon. Interestingly, C-terminally truncated PrP mutants have been linked to inherited prion disease in humans and are characterized by inefficient ER import and the formation of neurotoxic PrP conformers. In a recent study we found that the Sec61 translocon in eukaryotic cells as well as the SecY translocon in bacteria is inherently deficient in translocating intrinsically disordered proteins. Moreover, our results suggest that translocon-associated components in eukaryotic cells enable the Sec61 complex to transport secretory proteins with extended unstructured domains such as PrP and shadoo.

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The α-Helical Structure of Prodomains Promotes Translocation of Intrinsically Disordered Neuropeptide Hormones into the Endoplasmic Reticulum

Cited by 15 publications

References 73 publications

Two Dipolar α-Helices within Hormone-encoding Regions of Proglucagon Are Sorting Signals to the Regulated Secretory Pathway

Two Dipolar α-Helices within Hormone-encoding Regions of Proglucagon Are Sorting Signals to the Regulated Secretory Pathway

Coordinating antigen cytosolic delivery and danger signaling to program potent cross-priming by micelle-based nanovaccine

Impaired transport of intrinsically disordered proteins through the Sec61 and SecY translocon; implications for prion diseases

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