Neuroserpin is expressed in the pituitary and adrenal glands and induces the extension of neurite-like processes in AtT-20 cells

Hill, Rena M.; Parmar, Parmjeet K.; Coates, Leigh C.; Mezey, Éva; Pearson, John; Birch, Nigel P.

doi:10.1042/bj3450595

Cited by 39 publications

(20 citation statements)

References 42 publications

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“…Third, Spn4.1 has a C-terminal extension unique among the annotated Drosophila serpins but closely resembling the C-terminal region of neuroserpin (Osterwalder et al, 1996;Krueger et al, 1997;Schrimpf et al, 1997;Hill et al, 2000). Although the function of the C terminus of neuroserpin is not known, the Spn4.1 C terminus perfectly matches the K/H-D-E-L consensus for the ER retention signal for soluble proteins (Pelham, 1990), suggesting that this isoform functions in the secretory pathway.…”

Section: Discussionmentioning

confidence: 97%

DrosophilaSerpin 4 Functions as a Neuroserpin-Like Inhibitor of Subtilisin-Like Proprotein Convertases

Osterwalder

Kuhnen²,

Leiserson³

et al. 2004

J. Neurosci.

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The proteolytic processing of neuropeptide precursors is believed to be regulated by serine proteinase inhibitors, or serpins. Here we describe the molecular cloning and functional expression of a novel member of the serpin family, Serine protease inhibitor 4 (Spn4), that we propose is involved in the regulation of peptide maturation in Drosophila. The Spn4 gene encodes at least two different serpin proteins, generated by alternate splicing of the last coding exon. The closest vertebrate homolog to Spn4 is neuroserpin. Like neuroserpin, one of the Spn4 proteins (Spn4.1) features a unique C-terminal extension, reminiscent of an endoplasmic reticulum (ER) retention signal; however, Spn4.1 and neuroserpin have divergent reactive site loops, with Spn4.1 showing a generic recognition site for furin/SPC1, the founding member of the intracellularly active family of subtilisin-like proprotein convertases (SPCs). In vitro, Spn4.1 forms SDS-stable complexes with the SPC furin and directly inhibits it. When Spn4.1 is overexpressed in specific peptidergic cells of Drosophila larvae, the animals exhibit a phenotype consistent with disrupted neuropeptide processing. This observation, together with the unique combination of an ER-retention signal, a target sequence for SPCs in the reactive site loop, and the in vitro inhibitory activity against furin, strongly suggests that Spn4.1 is an intracellular regulator of SPCs.

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Section: Discussionmentioning

confidence: 97%

DrosophilaSerpin 4 Functions as a Neuroserpin-Like Inhibitor of Subtilisin-Like Proprotein Convertases

Osterwalder

Kuhnen²,

Leiserson³

et al. 2004

J. Neurosci.

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“…Neuroserpin is an axonally secreted member of the serine proteinase inhibitor or serpin superfamily (11)(12)(13)(14)(15). Members of this family share a similar molecular architecture based on a dominant ␤-sheet A and a mobile inhibitory reactive center loop (16).…”

mentioning

confidence: 99%

Mutant Neuroserpin (S49P) That Causes Familial Encephalopathy with Neuroserpin Inclusion Bodies Is a Poor Proteinase Inhibitor and Readily Forms Polymers in Vitro

Belorgey¹,

Crowther²,

Mahadeva³

et al. 2002

Journal of Biological Chemistry

152

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Familial encephalopathy with neuroserpin inclusion bodies (FENIB) is an autosomal dominant dementia؊1 and 533.3 nM, respectively. An assessment by circular dichroism showed that S49P neuroserpin had a lower melting temperature than wild-type protein (49.9 and 56.6°C, respectively) and more readily formed loop-sheet polymers under physiological conditions. Neither the wildtype nor S49P neuroserpin accepted the P7-P2 ␣ 1 -antitrypsin or P14-P3 antithrombin-reactive loop peptides that have been shown to block polymer formation in other members of the serpin superfamily. Taken together, these data demonstrate that S49P neuroserpin is a poor proteinase inhibitor and readily forms loop-sheet polymers. These findings provide strong support for the role of neuroserpin polymerization in the formation of the intraneuronal inclusions that are characteristic of FENIB.

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“…32 The effect of pH on the stability of neuroserpin is particularly important as this protein is stored in the acidic environment of the dense-core vesicles before secretion from the neurone. 20,[34][35][36] We report here that neuroserpin is resistant to polymer formation at acidic pH. This effect is not mediated by the shutter domain histidine but by other histidines, in particular His119 and His138.…”

Section: Introductionmentioning

confidence: 72%

“…37 The stabilization of neuroserpin at low pH may be physiologically relevant as neuroserpin is stored in the dense-core vesicles of cells that have a pH between 5.0 and 6.0, before its release in the extracellular environment. 20,[34][35][36] At neutral pH, the instability of neuroserpin might contribute to its faster clearance, either by forming unstable complexes with tPA 7,45 or by internalization by the LDL receptor-related protein. 46 In conclusion, this study showed the importance of the interaction between strand 1A and helix E in the polymerization of neuroserpin.…”

Section: Other Histidines Are Involved In Neuroserpin Polymerizationmentioning

confidence: 99%

pH‐dependent stability of neuroserpin is mediated by histidines 119 and 138; Implications for the control of β‐sheet A and polymerization

et al. 2010

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Neuroserpin is a member of the serpin superfamily. Point mutations in the neuroserpin gene underlie the autosomal dominant dementia, familial encephalopathy with neuroserpin inclusion bodies. This is characterized by the retention of ordered polymers of neuroserpin within the endoplasmic reticulum of neurons. pH has been shown to affect the propensity of several serpins to form polymers. In particular, low pH favors the formation of polymers of both a 1 -antitrypsin and antithrombin. We report here opposite effects in neuroserpin, with a striking resistance to polymer formation at acidic pH. Mutation of specific histidine residues showed that this effect is not attributable to the shutter domain histidine as would be predicted by analogy with other serpins. Indeed, mutation of the shutter domain His338 decreased neuroserpin stability but had no effect on the pH dependence of polymerization when compared with the wild-type protein.In contrast, mutation of His119 or His138 reduced the polymerization of neuroserpin at both acidic and neutral pH. These residues are at the lower pole of neuroserpin and provide a novel mechanism to control the opening of b-sheet A and hence polymerization. This mechanism is likely to have evolved to protect neuroserpin from the acidic environment of the secretory granules.

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Neuroserpin is expressed in the pituitary and adrenal glands and induces the extension of neurite-like processes in AtT-20 cells

Cited by 39 publications

References 42 publications

DrosophilaSerpin 4 Functions as a Neuroserpin-Like Inhibitor of Subtilisin-Like Proprotein Convertases

DrosophilaSerpin 4 Functions as a Neuroserpin-Like Inhibitor of Subtilisin-Like Proprotein Convertases

Mutant Neuroserpin (S49P) That Causes Familial Encephalopathy with Neuroserpin Inclusion Bodies Is a Poor Proteinase Inhibitor and Readily Forms Polymers in Vitro

pH‐dependent stability of neuroserpin is mediated by histidines 119 and 138; Implications for the control of β‐sheet A and polymerization

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