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Titolo:
PHORBOL ESTER-INDUCED JUXTAMEMBRANE CLEAVAGE OF ANGIOTENSIN-CONVERTING ENZYME IS NOT INHIBITED BY A STALK CONTAINING INTRACHAIN DISULFIDES
Autore:
SCHWAGER SLU; CHUBB AJ; SCHOLLE RR; BRANDT WF; ECKERSKORN C; STURROCK ED; EHLERS MRW;
Indirizzi:
BIONEBRASKA INC LINCOLN NE 68524 UNIV CAPE TOWN,SCH MED,DEPT BIOCHEM MED ZA-7925 OBSERVATORY SOUTH AFRICA UNIV CAPE TOWN,DEPT BIOCHEM ZA-7700 RONDEBOSCH SOUTH AFRICA MAX PLANCK INST BIOCHEM,PROT ANAL GRP D-82152 MARTINSRIED GERMANY
Titolo Testata:
Biochemistry (Easton)
fascicolo: 44, volume: 37, anno: 1998,
pagine: 15449 - 15456
SICI:
0006-2960(1998)37:44<15449:PEJCOA>2.0.ZU;2-G
Fonte:
ISI
Lingua:
ENG
Soggetto:
MEMBRANE-PROXIMAL CLEAVAGE; AMYLOID PRECURSOR PROTEIN; NECROSIS-FACTOR-ALPHA; HAMSTER OVARY CELLS; FACTOR-LIKE DOMAIN; GROWTH-FACTOR; L-SELECTIN; STRUCTURAL REQUIREMENTS; PROTEOLYTIC RELEASE; CRYSTAL-STRUCTURE;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Citazioni:
38
Recensione:
Indirizzi per estratti:
Citazione:
S.L.U. Schwager et al., "PHORBOL ESTER-INDUCED JUXTAMEMBRANE CLEAVAGE OF ANGIOTENSIN-CONVERTING ENZYME IS NOT INHIBITED BY A STALK CONTAINING INTRACHAIN DISULFIDES", Biochemistry (Easton), 37(44), 1998, pp. 15449-15456

Abstract

Specialized proteases, referred to as sheddases, secretases, or membrane-protein-solubilizing proteases (MPSPs), solubilize the extracellular domains of diverse membrane proteins by catalyzing a specific cleavage in the juxtamembrane stalk regions of such proteins. A representative MPSP (tumor necrosis factor-alpha convertase) was cloned recently and shown to be a disintegrin metalloprotease that is inhibited by peptide hydroxamates including the compound TAPI. Substrate determinants that specify cleavage by MPSPs remain incompletely characterized, bur may include the physicochemical properties of the stalk or unidentified recognition motifs in the stalk or the extracellular domain. We constructed a mutant angiotensin-converting enzyme (ACE) in which the stalk has been replaced with an epidermal growth factor (EGF)-like domain (ACE-JMEGF), to test the hypothesis that MPSP cleavage requires an open, comparatively unfolded or extended stalk. Wild-type ACE is a type Itransmembrane (TM) ectoprotein that is efficiently solubilized by a typical MPSP activity. We found that ACE-JMEGF was solubilized inefficiently and accumulated in a cell-associated form on transfected Chinesehamster ovary (CHO) cells; cleavage was stimulated by phorbol ester and inhibited by TAPI, features typical of MPSP activity. Determinationof the C-terminus of soluble ACE-JMEGF revealed that, surprisingly, cleavage occurred at a Gly-Phe bond between the fifth and sixth cysteines within the third disulfide loop of the EGF-like domain. Reduction of intact CHO cells with tributylphosphine resulted in the rapid release of ACE-JMEGF (but not wild-type ACE) into the medium, suggesting that a proportion of membrane-bound ACE-JMEGF is cleaved but remains cell-associated via disulfide tethering, The mechanism for the release of ACE-JMEGF in the absence of chemical reduction is unclear. We concludethat the presence of a compact, disulfide-bridged domain does not perse inhibit cleavage by an MPSP activity, but ectodomain release is prevented by disulfide tethering to the TM domain.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 24/09/20 alle ore 23:47:27