title: A truncated isoform of pyroglutamyl aminopeptidase II produced by exon extension has dominant-negative activity.
abstract: Thyrotropin-releasing hormone is inactivated in the extracellular space by a membrane-bound peptidase, pyroglutamyl aminopeptidase II (PPII), a member of the M1 family of zinc metallopeptidases. The functional significance of multiple PPII RNA species expression is unknown. We detected, in rat tissues, a RNA species derived from an alternative processing at the exon 14-intron 14 boundary. The alternatively processed RNA encoded a shorter version of PPII (PPII*), lacking part of the C-terminal domain. PPII* was expressed in COS-7 (or C6 glioma) cells but it did not exhibit any PPII activity. Co-transfection of PPII and increasing amounts of PPII* expression vectors resulted in a dose-dependent reduction in PPII activity and the formation of covalent PPII-PPII* heterodimers. PPII* is therefore a powerful dominant-negative isoform of PPII, and heterodimerization may be its mechanism of action. Natural expression of shortened versions of M1 aminopeptidases may constitute a new mode of regulation of their activity.
authors.affiliation: Departamento de Genética del Desarrollo y Fisiología Molecular, Instituto de Biotecnología, Universidad Nacional Autónoma de México, Cuernavaca, Morelos, México.
authors.forename: Lucia
authors.initials: L
authors.lastname: Chávez-Gutiérrez
authors.forename: Julie
authors.initials: J
authors.lastname: Bourdais
authors.forename: Gonzalo
authors.initials: G
authors.lastname: Aranda
authors.forename: Miguel Angel
authors.initials: MA
authors.lastname: Vargas
authors.forename: Edna
authors.initials: E
authors.lastname: Matta-Camacho
authors.forename: Frédéric
authors.initials: F
authors.lastname: Ducancel
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Segovia
authors.forename: Patricia
authors.initials: P
authors.lastname: Joseph-Bravo
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Charli
mesh_terms: D017398:Alternative Splicing; D000595:Amino Acid Sequence; D000626:Aminopeptidases / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics*; D000818:Animals; D001483:Base Sequence; D019556:COS Cells; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D004789:Enzyme Activation / Q000235:genetics; D005091:Exons / Q000235:genetics*; D006801:Humans; D007527:Isoenzymes / Q000096:biosynthesis / Q000235:genetics; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D011761:Pyrrolidonecarboxylic Acid / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar
chemical_list: D007527:Isoenzymes; D012333:RNA, Messenger; D000626:Aminopeptidases; C023166:pyroglutamyl-peptidase II; D011761:Pyrrolidonecarboxylic Acid