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 and Lorenzen, Inken (2017) GRP78 protects a disintegrin and metalloprotease 17 against protein-disulfide isomerase A6 catalyzed inactivation. FEBS Letters, 591 (21). pp. 3567-3587. DOI 10.1002/1873-3468.12858.

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Abstract

The shedding of ectodomains is a crucial mechanism in many physiological and pathological events. A disintegrin and metalloprotease-17 (ADAM17) is a key sheddase involved in essential processes, such as development, regeneration, and immune defense. ADAM17 exists in two conformations which differ in their disulfide connection in the membrane-proximal domain (MPD). Protein-disulfide isomerases (PDIs) on the cell surface convert the open MPD into a rigid closed form, which corresponds to inactive ADAM17. ADAM17 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-kDa glucose-regulated protein (GRP78) protects the MPD against PDI-dependent disulfide-bond isomerization by binding to this domain and, thereby, preventing ADAM17 inhibition.

Document Type:	Article
Keywords:	PDI ; ADAM17; BiP; GRP78; metalloprotease; thiol switch
Research affiliation:	Kiel University > Kiel Marine Science OceanRep > The Future Ocean - Cluster of Excellence
Refereed:	Yes
Open Access Journal?:	Yes
Publisher:	American Medical Association
Date Deposited:	08 Jan 2018 10:51
Last Modified:	13 May 2019 10:35
URI:	https://oceanrep.geomar.de/id/eprint/41248

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