GRP 78 protects a disintegrin and metalloprotease 17 against protein‐disulfide isomerase A6 catalyzed inactivation

• Published in: FEBS letters 2017-11, Vol.591 (21), p.3567-3587
• Main Authors: Schäfer, Miriam, Granato, Daniela C., Krossa, Sebastian, Bartels, Anne‐Kathrin, Yokoo, Sami, Düsterhöft, Stefan, Koudelka, Tomas, Scheidig, Axel J., Tholey, Andreas, Paes Leme, Adriana F., Grötzinger, Joachim, Lorenzen, Inken
• Format: Article
• Language: English
• ISSN: 0014-5793; 1873-3468
• DOI: 10.1002/1873-3468.12858

The shedding of ectodomains is a crucial mechanism in many physiological and pathological events. A disintegrin and metalloprotease‐17 ( ADAM 17) is a key sheddase involved in essential processes, such as development, regeneration, and immune defense. ADAM 17 exists in two conformations which differ in their disulfide connection in the membrane‐proximal domain ( MPD ). Protein‐disulfide isomerases ( PDI s) on the cell surface convert the open MPD into a rigid closed form, which corresponds to inactive ADAM 17. ADAM 17 is expressed in its open activatable form in the endoplasmic reticulum ( ER ) and consequently must be protected against ER ‐resident PDI activity. Here, we show that the chaperone 78‐ kD a glucose‐regulated protein ( GRP 78) protects the MPD against PDI ‐dependent disulfide‐bond isomerization by binding to this domain and, thereby, preventing ADAM 17 inhibition.