Lumenal protein multimerization in the distal secretory pathway/secretory granules

Arvan, Peter; Zhang, Bao Yan; Li, Feng; Liu, Ming; Kuliawat, Regina

doi:10.1016/s0955-0674(02)00344-7

Cited by 51 publications

(28 citation statements)

References 67 publications

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“…The storage of VWF in Weibel-Palade bodies resembles the reversible concentration of cargo proteins within the secretory granules of other cells, particularly in neuroendocrine tissues (25,26). Protein self-aggregation in the trans-Golgi network is also the initial step in the biogenesis of these granules.…”

Section: Discussionmentioning

confidence: 99%

Assembly of Weibel–Palade body-like tubules from N-terminal domains of von Willebrand factor

Huang

Wang²,

Roth³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

149

285

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Lengthwise sections show longitudinal striations, and cross sections reveal closely spaced Ϸ20-nm diameter tubules separated by a less-dense matrix (1). Weibel-Palade bodies are composed almost entirely of von Willebrand factor (VWF) (2, 3), which is a multimeric plasma glycoprotein that can exceed 20 million Da in mass and 4 m in length. Megakaryocytes synthesize large VWF multimers and package them into platelet ␣-granules that are roughly spherical rather than cigar-shaped. Nevertheless, the VWF multimers in ␣-granules are organized into clusters of tubules with dimensions similar to those of VWF tubules in Weibel-Palade bodies (4). VWF is the largest known protein in the blood, and the very largest VWF multimers bind connective tissue and mediate platelet adhesion at sites of vascular injury. Weibel-Palade bodies play a critical role in hemostasis by delivering VWF multimers into the circulation. Defects in VWF multimer structure cause several forms of von Willebrand disease, the most common inherited bleeding disorder worldwide (5).VWF is synthesized as an Ϸ350-kDa precursor with a signal peptide and five kinds of structural domains arranged in the order D1-D2-DЈ-D3-A1-A2-A3-D4-B1-B2-B3-C1-C2-CK ( Fig. 1) (5). In the endoplasmic reticulum (ER), proVWF dimerizes through disulfide bonds between C-terminal CK domains (6-8).The resultant ''tail-to-tail'' proVWF dimers are transported to the Golgi, where the propeptide (domains D1D2) is cleaved by furin and additional ''head-to-head'' disulfide bonds form between D3 domains, yielding multimers that condense into tubules and form Weibel-Palade bodies (6, 9).In fact, the expression of VWF determines the existence and also the cigar-like shape of Weibel-Palade bodies. Without VWF, endothelial cells lack Weibel-Palade bodies (10, 11), and the expression of VWF in other cell types that have a regulated secretory pathway results in the generation of organelles that are indistinguishable from Weibel-Palade bodies (12, 13). This self-organizing behavior depends on a conserved set of Nterminal domains that have the dual function of promoting multimer assembly and directing tubular storage.Multimer assembly (14-16) and tubular packing (12, 17) both depend on the N-terminal D1D2DЈD3 domains and require the acidic pH of the late secretory pathway (13). Furthermore, the tubular morphology of Weibel-Palade bodies is essential for . VWF multimers are held together by intersubunit disulfide bonds between CK domains, which form in the ER, and by intersubunit disulfide bonds between D3 domains, which form in the Golgi. The structures of polypeptides encoded by the plasmids used in these studies are indicated.

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Section: Discussionmentioning

confidence: 99%

Assembly of Weibel–Palade body-like tubules from N-terminal domains of von Willebrand factor

Huang

Wang²,

Roth³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

149

285

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“…In endocrine, neuroendocrine, and exocrine cells, these proteins are stored in post-Golgi secretory granules that secrete their content only upon stimulation. The cell biology of these proteins has attracted the interest of researchers who study seed storage proteins, because the formation of highly condensed polymers has a role in sorting into secretory granules (Arvan et al, 2002;Vitale and Hinz, 2005). Unstimulated secretion of newly synthesized chromogranin B was observed in PC-12 nerve cells treated with DTT, implying a role of disulfide bonds in the sorting into secretory granules and therefore in preventing default secretion (Chanat et al, 1993;Gorr et al, 1999).…”

Section: Comparison With Other Systemsmentioning

confidence: 99%

Retention of a Bean Phaseolin/Maize γ-Zein Fusion in the Endoplasmic Reticulum Depends on Disulfide Bond Formation

Pompa

Vitale

2006

The Plant Cell

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Most seed storage proteins of the prolamin class accumulate in the endoplasmic reticulum (ER) as large insoluble polymers termed protein bodies (PBs), through mechanisms that are still poorly understood. We previously showed that a fusion between the Phaseolus vulgaris vacuolar storage protein phaseolin and the N-terminal half of the Zea mays prolamin g-zein forms ER-located PBs. Zeolin has 6 Cys residues and, like g-zein with 15 residues, is insoluble unless reduced. The contribution of disulfide bonds to zeolin destiny was determined by studying in vivo the effects of 2-mercaptoethanol (2-ME) and by zeolin mutagenesis. We show that in tobacco (Nicotiana tabacum) protoplasts, 2-ME enhances interactions of newly synthesized proteins with the ER chaperone BiP and inhibits the secretory traffic of soluble proteins with or without disulfide bonds. In spite of this general inhibition, 2-ME enhances the solubility of zeolin and relieves its retention in the ER, resulting in increased zeolin traffic. Consistently, mutated zeolin unable to form disulfide bonds is soluble and efficiently enters the secretory traffic without 2-ME treatment. We conclude that disulfide bonds that lead to insolubilization are a determinant for PB-mediated protein accumulation in the ER.

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“…Failure to secrete the single-chain insulin moiety cannot be explained by ICFP endoproteolysis within a "dead-end" compartment from which molecules can no longer be secreted, because simple deletion of the yeast KEX2 gene not only prevents ICFP processing but also increases the quantity of ICFP secreted. It is known that by liberating insulin from its precursor (in either mammalian cells or yeast), cleavage promotes a change in the biophysical properties of the processed product (5)(6)(7)(8)(9)(10)(11), and this might play a role in protein sorting in the lumen of the distal secretory pathway (12,13).…”

mentioning

confidence: 99%

Behavior in the Eukaryotic Secretory Pathway of Insulin-containing Fusion Proteins and Single-chain Insulins Bearing Various B-chain Mutations

Zhang¹,

Liu²,

Arvan³

2003

Journal of Biological Chemistry

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In the secretory pathway, endoproteolytic cleavage of the insulin precursor protein promotes a change in the biophysical properties of the processed insulin product, and this may be relevant for its intracellular trafficking. We have now studied several independent point mutants contained within the insulin B-chain, S9D, H10D, V12E (called B9D, B10D, and B12E), as well as the double point mutant P28K,K29P (B28K,B29P), that have been reported to inhibit insulin oligomerization. In yeast cells, the unprocessed precursor of each of these mutants is secreted, whereas >90% of the endoproteolytically released single-chain insulin moiety is retained intracellularly; a large portion of the B9D, B10D, and B12E single-chain insulins exhibit abnormally slow mobility upon nonreducing SDS-PAGE, despite normal mobility upon reducing SDS-PAGE. Although no free thiols can be detected, each of these mutants exhibits increased disulfide accessibility to dithiothreitol. After dithiothreitol treatment, a portion of the molecules can reoxidize to a form more compact than the original single-chain insulin mutants formed in vivo (indicating initial disulfide mispairing). Disulfide mispairing of a fraction of B9D, B10D, and B12E mutants also occurs in the context of single-chain insulin and even in authentic proinsulin expressed within the secretory pathway of mammalian cells. We conclude that analyses of the intracellular trafficking of certain oligomerization-defective insulin mutants is complicated by the formation of disulfide isomers in the secretory pathway.

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Lumenal protein multimerization in the distal secretory pathway/secretory granules

Cited by 51 publications

References 67 publications

Assembly of Weibel–Palade body-like tubules from N-terminal domains of von Willebrand factor

Assembly of Weibel–Palade body-like tubules from N-terminal domains of von Willebrand factor

Retention of a Bean Phaseolin/Maize γ-Zein Fusion in the Endoplasmic Reticulum Depends on Disulfide Bond Formation

Behavior in the Eukaryotic Secretory Pathway of Insulin-containing Fusion Proteins and Single-chain Insulins Bearing Various B-chain Mutations

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