GRP78 protects a disintegrin and metalloprotease 17 against protein‐disulfide isomerase A6 catalyzed inactivation

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...

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Bibliographic Details
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
Subjects:
ADAM17
ADAM17 Protein - metabolism
BiP
Endoplasmic Reticulum - genetics
Endoplasmic Reticulum - metabolism
Enzyme Activation
GRP78
Heat-Shock Proteins - genetics
Heat-Shock Proteins - metabolism
HEK293 Cells
Humans
metalloprotease
PDI
Protein Disulfide-Isomerases - genetics
Protein Disulfide-Isomerases - metabolism
Protein Domains
thiol switch
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Summary: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.
ISSN:0014-5793
1873-3468
DOI:10.1002/1873-3468.12858