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Titolo:
Roles of the juxtamembrane and extracellular domains of angiotensin-converting enzyme in ectodomain shedding
Autore:
Pang, S; Chubb, AJ; Schwager, SLU; Ehlers, MRW; Sturrock, ED; Hooper, NM;
Indirizzi:
Univ Leeds, Sch Biochem & Mol Biol, Proteolysis Res Grp, Leeds LS2 9JT, W Yorkshire, England Univ Leeds Leeds W Yorkshire England LS2 9JT S2 9JT, W Yorkshire, England Univ Cape Town, Dept Med Biochem, ZA-7700 Rondebosch, South Africa Univ Cape Town Rondebosch South Africa ZA-7700 Rondebosch, South Africa BioNebraska Inc, Lincoln, NE 68524 USA BioNebraska Inc Lincoln NE USA 68524 oNebraska Inc, Lincoln, NE 68524 USA
Titolo Testata:
BIOCHEMICAL JOURNAL
, volume: 358, anno: 2001,
parte:, 1
pagine: 185 - 192
SICI:
0264-6021(20010815)358:<185:ROTJAE>2.0.ZU;2-Y
Fonte:
ISI
Lingua:
ENG
Soggetto:
NECROSIS-FACTOR-ALPHA; AMYLOID PRECURSOR PROTEIN; ZINC METALLOPROTEASE INHIBITORS; RENAL DIPEPTIDASE; TRANSMEMBRANE PROTEINS; MEMBRANE DIPEPTIDASE; MOLECULAR-CLONING; PHOSPHOLIPASE-C; STALK SEQUENCE; PHORBOL ESTER;
Keywords:
batimastat; membrane dipeptidase; secretase; zinc metalloprotease;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
45
Recensione:
Indirizzi per estratti:
Indirizzo: Hooper, NM Univ Leeds, Sch Biochem & Mol Biol, Proteolysis Res Grp, Leeds LS2 9JT, W Yorkshire, England Univ Leeds Leeds W Yorkshire England LS2 9JTorkshire, England
Citazione:
S. Pang et al., "Roles of the juxtamembrane and extracellular domains of angiotensin-converting enzyme in ectodomain shedding", BIOCHEM J, 358, 2001, pp. 185-192

Abstract

Angiotensin-converting enzyme (ACE) is one of a growing number of integralmembrane proteins that is shed from the cell surface through proteolytic cleavage by a secretase. To investigate the requirements for ectodomain shedding, we replaced the glycosylphosphatidylinositol addition sequence in membrane dipeptidase (MDP) - a membrane protein that is not shed - with the juxtamembrane stalk, transmembrane (TM) and cytosolic domains of ACE. The resulting construct, MDP STM,,,,, was targeted to the cell surface in a glycosylated and enzymically active form, and was shed into the medium. The site of cleavage in MDP-STMACE was identified by MS as the Arg(374)-Ser(375) bond, corresponding to the Arg(1203)-Ser(1204) secretase cleavage site in somatic ACE. The release of MDP-STMACE and ACE from the cells was inhibited in an identical manner by batimastat and two other hydroxamic acid-based zinc metallosecretase inhibitors. In contrast, a construct lacking the juxtamembrane stalk, MDP-TMACE, although expressed at the cell surface in an enzymically active form, was not shed, implying that the juxtamembrane stalk is the critical determinant of shedding. However, an additional construct, ACE DeltaC, in which the N-terminal domain of somatic ACE was fused to the stalk, TM and cytosolic domains, was also not shed, despite the presence of a cleavable stalk, implying that in contrast with the C-terminal domain, the N-terminal domain lacks a signal required for shedding. These data are discussed in the context of two classes of secretases that differ in their requirements for recognition of substrate proteins.

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Documento generato il 30/10/20 alle ore 08:53:53