Alpha-secretase activity of the disintegrin metalloprotease ADAM 10. Influences of domain structure.
Disintegrin metalloproteases from different organisms form the ADAM (a disintegrin and metalloprotease) family. All members display a common domain organization and possess four potential functions: proteolysis, cell adhesion, cell fusion, and cell signaling. Members of the ADAM family are responsible for the proteolytic cleavage of transmembrane proteins and release of their extracellular domain. The proteolytic process is referred to as ectodomain shedding, which is activated by phorbol esters and inhibited by hydroxamic acid-based inhibitors. We have shown that the disintegrin metalloprotease ADAM 10 has both constitutive and regulated alpha-secretase activity. Expression of a dominant negative mutant of ADAM 10 in HEK cells decreases the secretion of APPs alpha. In order to investigate the influence of distinct protein domains of ADAM 10 on alpha-secretase activity, several deletion mutants of ADAM 10 were constructed. Our findings demonstrate that the deletion of the disintegrin domain results in a mutant ADAM 10 with remaining alpha-secretase activity, whereas the deletion of the prodomain destroys the proteolytic activity of ADAM 10.
Fahrenholz
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F
Institut für Biochemie, Johannes Gutenberg-Universität, Becherweg 30, D-55128 Mainz, Germany. ibc1950@mail.uni-mainz.de
Gilbert
S
S
Kojro
E
E
Lammich
S
S
Postina
R
R
D051722:ADAM Proteins; D000072197:ADAM10 Protein; D000595:Amino Acid Sequence; D053829:Amyloid Precursor Protein Secretases; D016564:Amyloid beta-Protein Precursor / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D016282:Aspartic Acid Endopeptidases; D019483:Disintegrins / Q000378:metabolism; D010450:Endopeptidases / Q000378:metabolism*; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D008666:Metalloendopeptidases / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D011480:Protease Inhibitors / Q000494:pharmacology; D011499:Protein Processing, Post-Translational; D011994:Recombinant Proteins / Q000378:metabolism
D016564:Amyloid beta-Protein Precursor; D019483:Disintegrins; D008565:Membrane Proteins; D011480:Protease Inhibitors; D011994:Recombinant Proteins; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human; D051722:ADAM Proteins; D008666:Metalloendopeptidases; D000072197:ADAM10 Protein; C491236:ADAM10 protein, human