The Spn4 gene of Drosophila encodes a potent furin-directed secretory pathway serpin

Proceedings of the National Academy of Sciences of the United States of America
Martin J RicherFrançois Jean

Abstract

Proprotein convertases (PCs) are an important class of host-cell serine endoproteases implicated in many physiological and pathological processes. Owing to their expanding roles in the proteolytic events required for generating infectious microbial pathogens and for tumor growth and invasiveness, there is increasing interest in identifying endogenous PC inhibitors. Here we report the identification of Spn4A, a previously uncharacterized secretory pathway serine protease inhibitor (serpin) from Drosophila melanogaster that contains a consensus furin cleavage site, -Arg(P4)-Arg-Lys-Arg(P1) downsream-, in its reactive site loop (RSL). Our biochemical and kinetics analysis revealed that recombinant Spn4A inhibits human furin (K(i), 13 pM; k(ass), 3.2 x 10(7) M(-1) x s(-1)) and Drosophila PC2 (K(i), 3.5 nM; k(ass), 9.2 x 10(4) M(-1) x s(-1)) by a slow-binding mechanism characteristic of serpin molecules and forms a kinetically trapped SDS-stable complex with each enzyme. For both PCs, the stoichiometry of inhibition by Spn4A is nearly 1, which is characteristic of known physiological serpin-protease interactions. Mass analysis of furin-Spn4A reaction products identified the actual reactive site center of Spn4A to be -Arg(P4)-Arg-Lys...Continue Reading

References

Aug 1, 1991·Current Opinion in Cell Biology·H R Pelham
Jan 27, 1998·The Journal of Biological Chemistry·J R DahlenW Kisiel
Jun 24, 1998·Proceedings of the National Academy of Sciences of the United States of America·F JeanG Thomas
Jun 9, 1999·DNA and Cell Biology·M Fahnestock, W Zhu
Jul 20, 1999·The Journal of Biological Chemistry·A ZhouD F Steiner
Oct 3, 1999·Progress in Nucleic Acid Research and Molecular Biology·L Muller, I Lindberg
Feb 5, 2000·Journal of Molecular Endocrinology·F BergeronR Day
Feb 19, 2000·Proceedings of the National Academy of Sciences of the United States of America·F JeanG Thomas
Feb 29, 2000·FEBS Letters·J HanC Hashimoto
Oct 26, 2000·Proceedings of the National Academy of Sciences of the United States of America·J BassD F Steiner
Apr 28, 2001·The Journal of Biological Chemistry·A ZhouJ A Huntington
Jul 4, 2001·The Journal of Biological Chemistry·A BasakN G Seidah
Jul 6, 2001·The Biochemical Journal·M MbikayM Chrétien
Nov 24, 2001·The Journal of Biological Chemistry·Yolanda FortenberryIris Lindberg
Oct 3, 2002·Nature Reviews. Molecular Cell Biology·Gary Thomas
Dec 5, 2002·Essays in Biochemistry·Nabil G Seidah, Annik Prat
Dec 12, 2002·Chemical Reviews·Nathan C RockwellRobert S Fuller
Dec 12, 2002·Chemical Reviews·Peter G W Gettins
Jun 26, 2003·The International Journal of Biochemistry & Cell Biology·Diana van GentNoor Kalsheker
Dec 12, 2003·Developmental Cell·Carl HashimotoDonald Morisato

❮ Previous
Next ❯

Citations

Jun 1, 2005·Trends in Pharmacological Sciences·Martin Fugère, Robert Day
Oct 28, 2009·The Journal of Biological Chemistry·Rui JiangBok-Luel Lee
Dec 16, 2011·Molecular Pharmacology·Mirella VivoliIris Lindberg
May 18, 2011·Molecular and Cellular Biology·Ane FullaondoDavid Gubb
Aug 21, 2013·Genome Génome / Conseil National De Recherches Canada·Zhao-Yu GeZhao-Jun Han
Jan 11, 2008·Annual Review of Pharmacology and Toxicology·Vivian HookShin-Rong Hwang
Dec 2, 2005·Neuroendocrinology·Dorien M de GrootGerard J M Martens
Sep 17, 2008·BMC Evolutionary Biology·Abhishek Kumar, Hermann Ragg
Aug 18, 2006·Biological Chemistry·Nabil G SeidahAnnik Prat
Apr 25, 2014·BMC Structural Biology·Andrew M EllisdonJames C Whisstock
Dec 21, 2006·Proceedings of the National Academy of Sciences of the United States of America·Guan-Sheng JiaoGary Thomas
Nov 9, 2010·Infection, Genetics and Evolution : Journal of Molecular Epidemiology and Evolutionary Genetics in Infectious Diseases·Sarah MwangiAlan Christoffels
Sep 21, 2010·Biochimie·David GubbAne Fullaondo
Apr 28, 2009·Gene·Chansak Suwanchaichinda, Michael R Kanost
Oct 31, 2012·Molecular Reproduction and Development·Brooke A Laflamme, Mariana F Wolfner
Nov 2, 2005·Trends in Cell Biology·Jean-Marc Reichhart
Sep 11, 2008·Expert Opinion on Therapeutic Targets·Michel ChrétienMajambu Mbikay
Jan 20, 2009·Genomics·Zhen ZouHaobo Jiang
Sep 8, 2016·Seminars in Cell & Developmental Biology·David A MeekinsKristin Michel
Nov 6, 2004·FEBS Letters·Mareke OleyHermann Ragg
Jul 12, 2007·The Journal of Biological Chemistry·Philomena PullikotilNabil G Seidah
Mar 22, 2021·Molecular Biology and Evolution·Matthew A SpenceColin J Jackson

❮ Previous
Next ❯

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.