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Substrate‐selective protein ectodomain shedding by ADAM17 and iRhom2 depends on their juxtamembrane and transmembrane domains
Author(s) -
Tang Beiyu,
Li Xue,
Maretzky Thorsten,
PerezAguilar Jose Manuel,
McIlwain David,
Xie Yifang,
Zheng Yufang,
Mak Tak W.,
Weinstein Harel,
Blobel Carl P.
Publication year - 2020
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.201902649r
Subject(s) - ectodomain , disintegrin , metalloproteinase , epidermal growth factor , microbiology and biotechnology , epidermal growth factor receptor , transmembrane domain , chemistry , transmembrane protein , mutant , biology , receptor , biochemistry , matrix metalloproteinase , gene
The metalloprotease ADAM17 (a disintegrin and metalloprotease 17) regulates EGF‐receptor and TNFα signaling, thereby not only protecting the skin and intestinal barrier, but also contributing to autoimmunity. ADAM17 can be rapidly activated by many stimuli through its transmembrane domain (TMD), with the seven membrane‐spanning inactive Rhomboids (iRhom) 1 and 2 implicated as candidate regulatory partners. However, several alternative models of ADAM17 regulation exist that do not involve the iRhoms, such as regulation through disulfide bond exchange or through interaction with charged phospholipids. Here, we report that a non‐activatable mutant of ADAM17 with the TMD of betacellulin (BTC) can be rescued by restoring residues from the ADAM17 TMD, but only in Adam17 −/− cells, which contain iRhoms, not in iRhom1/2 −/− cells. We also provide the first evidence that the extracellular juxtamembrane domains (JMDs) of ADAM17 and iRhom2 regulate the stimulation and substrate selectivity of ADAM17. Interestingly, a point mutation in the ADAM17 JMD identified in a patient with Tetralogy of Fallot, a serious heart valve defect, affects the substrate selectivity of ADAM17 toward Heparin‐binding epidermal growth factor like growth factor (HB‐EGF), a crucial regulator of heart valve development in mice. These findings provide new insights into the regulation of ADAM17 through an essential interaction with the TMD1 and JMD1 of iRhom2.