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The Journal of Neuroscience, June 16, 2004, 24(24):5482-5491; doi:10.1523/JNEUROSCI.5577-03.2004

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Behavioral/Systems/Cognitive
Drosophila Serpin 4 Functions as a Neuroserpin-Like Inhibitor of Subtilisin-Like Proprotein Convertases

Thomas Osterwalder, Angela Kuhnen, William M. Leiserson, You-Seung Kim, and Haig Keshishian

Department of Molecular, Cellular, and Developmental Biology, Yale University, New Haven, Connecticut 06520-8103

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.

Key words: neuroserpin; proprotein convertase; Drosophila; neuropeptide; ecdysis; neurosecretion; serine protease

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Received June 25, 2003; revised April 20, 2004; accepted April 22, 2004.

This article has been cited by other articles:

				S. T. Ahmad, S. T. Sweeney, J.-A Lee, N. T. Sweeney, and F.-B. Gao Genetic screen identifies serpin5 as a regulator of the toll pathway and CHMP2B toxicity associated with frontotemporal dementia PNAS, July 21, 2009; 106(29): 12168 - 12173. [Abstract] [Full Text] [PDF]

				D. M. de Groot and G. J. M. Martens Expression of Neuroserpin Is Linked to Neuroendocrine Cell Activation Endocrinology, September 1, 2005; 146(9): 3791 - 3799. [Abstract] [Full Text] [PDF]

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