Substrate-selective protein ectodomain shedding by ADAM17 and iRhom2 depends on their juxtamembrane and transmembrane domains

Beiyu Tang; Xue Li; Thorsten Maretzky; Jose Manuel Perez-Aguilar; David McIlwain; Yifang Xie; Yufang Zheng; Tak W. Mak; Harel Weinstein; Carl P. Blobel

doi:10.1096/fj.201902649R

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Substrate-selective protein ectodomain shedding by ADAM17 and iRhom2 depends on their juxtamembrane and transmembrane domains

Journal article

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Substrate-selective protein ectodomain shedding by ADAM17 and iRhom2 depends on their juxtamembrane and transmembrane domains

Beiyu Tang, Xue Li, Thorsten Maretzky, Jose Manuel Perez-Aguilar, David McIlwain, Yifang Xie, Yufang Zheng, Tak W. Mak, Harel Weinstein and Carl P. Blobel

The FASEB journal, Vol.34(4), pp.4956-4969

04/01/2020

DOI: 10.1096/fj.201902649R

PMCID: PMC7316530

PMID: 32103528

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Abstract

The metalloprotease ADAM17 (a disintegrin and metalloprotease 17) regulates EGF-receptor and TNF alpha 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.

Biochemistry & Molecular Biology

Biology

Cell Biology

Life Sciences & Biomedicine

Life Sciences & Biomedicine - Other Topics

Science & Technology

Details

Title: Subtitle: Substrate-selective protein ectodomain shedding by ADAM17 and iRhom2 depends on their juxtamembrane and transmembrane domains
Creators: Beiyu Tang - Hospital for Special Surgery
Xue Li - Hospital for Special Surgery
Thorsten Maretzky - Roy J. and Lucille A. Carver College of Medicine
Jose Manuel Perez-Aguilar - Cornell University
David McIlwain - Stanford University
Yifang Xie - Fudan University
Yufang Zheng - Fudan University
Tak W. Mak - Princess Margaret Cancer Centre
Harel Weinstein - Cornell University
Carl P. Blobel - Hospital for Special Surgery
Resource Type: Journal article
Publication Details: The FASEB journal, Vol.34(4), pp.4956-4969
DOI: 10.1096/fj.201902649R
PMID: 32103528
PMCID: PMC7316530
NLM abbreviation: FASEB J
ISSN: 0892-6638
eISSN: 1530-6860
Publisher: Wiley
Number of pages: 14
Grant note: R01 GM64750; R35 GM134907 / HHS | National Institutes of Health (NIH); United States Department of Health & Human Services; National Institutes of Health (NIH) - USA
Language: English
Date published: 04/01/2020
Academic Unit: Internal Medicine
Record Identifier: 9984359914402771

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