Thiol isomerases negatively regulate the cellular shedding activity of ADAM17.

Sofie H Willems (1) , Christopher James Tape , Peter L. D. Stanley , Neil A Taylor , Ian G Mills , David E Neal , John Mccafferty , Gillian Murphy

1 Oncology

The disintegrin metalloprotease ADAM17 can rapidly modulate cell surface signalling events by the proteolytic release of soluble forms of pro-ligands for cellular receptors. Many regulatory pathways effect ADAM17 sheddase activity, but the mechanisms for its activation are still not clear. We have utilized a cell based ADAM17 assay to show that thiol isomerases, specifically protein disulphide isomerase, could be responsible for maintaining ADAM17 in an inactive form. Down regulation of thiol isomerases, by changes in the redox environment, for instance as elicited by phorbol ester modulation of mitochondrial reactive oxygen species, markedly enhanced ADAM17 activation. Based on ELISA binding studies with novel fragment antibodies to ADAM17 we propose that isomerisation of the disulphide bonds in ADAM17 and the subsequent conformational changes form the basis for the modulation of ADAM17 activity. The shuffling of disulphide bond patterns in ADAMs has been suggested by a number of recent adamalysin crystal structures, with distinct disulphide bond patterns altering the relative orientations of the domains. Such a mechanism is rapid and reversible and the role of thiol isomerases should be investigated further as a potential factor in the redox regulation of ADAM17.

Mots clés: Life Sciences

Sofie H Willems, Christopher James Tape, Peter L. D. Stanley, Neil A Taylor, Ian G Mills, et al.. Thiol isomerases negatively regulate the cellular shedding activity of ADAM17.. Biochemical Journal, 2010, 428 (3), pp.439-450. ⟨10.1042/BJ20100179⟩. ⟨hal-00486862⟩