Identification of Molecular Determinants in iRhoms1 and 2 That Contribute to the Substrate Selectivity of Stimulated ADAM17
The metalloprotease ADAM17 is a key regulator of the TNFα, IL-6R and EGFR signaling pathways. The maturation and function of ADAM17 is controlled by the seven-membrane-spanning proteins iRhoms1 and 2. The functional properties of the ADAM17/iRhom1 and ADAM17/iRhom2 complexes differ, in that stimulat...
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| Format: | Article |
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2022-10-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/23/21/12796 |
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| author | Yi Zhao Eliud Morales Dávila Xue Li Beiyu Tang Ariana I. Rabinowitsch Jose Manuel Perez-Aguilar Carl P. Blobel |
| author_facet | Yi Zhao Eliud Morales Dávila Xue Li Beiyu Tang Ariana I. Rabinowitsch Jose Manuel Perez-Aguilar Carl P. Blobel |
| author_sort | Yi Zhao |
| collection | DOAJ |
| description | The metalloprotease ADAM17 is a key regulator of the TNFα, IL-6R and EGFR signaling pathways. The maturation and function of ADAM17 is controlled by the seven-membrane-spanning proteins iRhoms1 and 2. The functional properties of the ADAM17/iRhom1 and ADAM17/iRhom2 complexes differ, in that stimulated shedding of most ADAM17 substrates tested to date can be supported by iRhom2, whereas iRhom1 can only support stimulated shedding of very few ADAM17 substrates, such as TGFα. The first transmembrane domain (TMD1) of iRhom2 and the sole TMD of ADAM17 are important for the stimulated shedding of ADAM17 substrates by iRhom2. However, little is currently known about how the iRhoms interact with different substrates to control their stimulated shedding by ADAM17. To provide new insights into this topic, we tested how various chimeras between iRhom1 and iRhom2 affect the stimulated processing of the EGFR-ligands TGFα (iRhom1- or 2-dependent) and EREG (iRhom2-selective) by ADAM17. This uncovered an important role for the TMD7 of the iRhoms in determining their substrate selectivity. Computational methods utilized to characterize the iRhom1/2/substrate interactions suggest that the substrate selectivity is determined, at least in part, by a distinct accessibility of the substrate cleavage site to stimulated ADAM17. These studies not only provide new insights into why the substrate selectivity of stimulated iRhom2/ADAM17 differs from that of iRhom1/ADAM17, but also suggest new approaches for targeting the release of specific ADAM17 substrates. |
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| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T19:02:02Z |
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| spelling | doaj.art-df8df69f016e4ae18d9d78c59a6d11322023-11-24T04:57:19ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-10-0123211279610.3390/ijms232112796Identification of Molecular Determinants in iRhoms1 and 2 That Contribute to the Substrate Selectivity of Stimulated ADAM17Yi Zhao0Eliud Morales Dávila1Xue Li2Beiyu Tang3Ariana I. Rabinowitsch4Jose Manuel Perez-Aguilar5Carl P. Blobel6Department of Biochemistry, Cellular and Molecular Biology, Weill Cornell Medicine, New York, NY 10021, USASchool of Chemical Sciences, Meritorious Autonomous University of Puebla (BUAP), University City, Puebla 72570, MexicoDepartment of Biochemistry, Cellular and Molecular Biology, Weill Cornell Medicine, New York, NY 10021, USADepartment of Pharmacology, Weill Cornell Medicine, New York, NY 10021, USADepartment of Biochemistry, Cellular and Molecular Biology, Weill Cornell Medicine, New York, NY 10021, USASchool of Chemical Sciences, Meritorious Autonomous University of Puebla (BUAP), University City, Puebla 72570, MexicoDepartment of Physiology, Biophysics and Systems Biology, Weill Cornell Medicine, New York, NY 10021, USAThe metalloprotease ADAM17 is a key regulator of the TNFα, IL-6R and EGFR signaling pathways. The maturation and function of ADAM17 is controlled by the seven-membrane-spanning proteins iRhoms1 and 2. The functional properties of the ADAM17/iRhom1 and ADAM17/iRhom2 complexes differ, in that stimulated shedding of most ADAM17 substrates tested to date can be supported by iRhom2, whereas iRhom1 can only support stimulated shedding of very few ADAM17 substrates, such as TGFα. The first transmembrane domain (TMD1) of iRhom2 and the sole TMD of ADAM17 are important for the stimulated shedding of ADAM17 substrates by iRhom2. However, little is currently known about how the iRhoms interact with different substrates to control their stimulated shedding by ADAM17. To provide new insights into this topic, we tested how various chimeras between iRhom1 and iRhom2 affect the stimulated processing of the EGFR-ligands TGFα (iRhom1- or 2-dependent) and EREG (iRhom2-selective) by ADAM17. This uncovered an important role for the TMD7 of the iRhoms in determining their substrate selectivity. Computational methods utilized to characterize the iRhom1/2/substrate interactions suggest that the substrate selectivity is determined, at least in part, by a distinct accessibility of the substrate cleavage site to stimulated ADAM17. These studies not only provide new insights into why the substrate selectivity of stimulated iRhom2/ADAM17 differs from that of iRhom1/ADAM17, but also suggest new approaches for targeting the release of specific ADAM17 substrates.https://www.mdpi.com/1422-0067/23/21/12796ADAM17 (a disintegrin and metalloprotease 17)iRhom1 and 2 (inactive rhomboid like protein 1 and 2)EGFR-ligand (epidermal growth factor receptor ligand)protein ectodomain shedding |
| spellingShingle | Yi Zhao Eliud Morales Dávila Xue Li Beiyu Tang Ariana I. Rabinowitsch Jose Manuel Perez-Aguilar Carl P. Blobel Identification of Molecular Determinants in iRhoms1 and 2 That Contribute to the Substrate Selectivity of Stimulated ADAM17 International Journal of Molecular Sciences ADAM17 (a disintegrin and metalloprotease 17) iRhom1 and 2 (inactive rhomboid like protein 1 and 2) EGFR-ligand (epidermal growth factor receptor ligand) protein ectodomain shedding |
| title | Identification of Molecular Determinants in iRhoms1 and 2 That Contribute to the Substrate Selectivity of Stimulated ADAM17 |
| title_full | Identification of Molecular Determinants in iRhoms1 and 2 That Contribute to the Substrate Selectivity of Stimulated ADAM17 |
| title_fullStr | Identification of Molecular Determinants in iRhoms1 and 2 That Contribute to the Substrate Selectivity of Stimulated ADAM17 |
| title_full_unstemmed | Identification of Molecular Determinants in iRhoms1 and 2 That Contribute to the Substrate Selectivity of Stimulated ADAM17 |
| title_short | Identification of Molecular Determinants in iRhoms1 and 2 That Contribute to the Substrate Selectivity of Stimulated ADAM17 |
| title_sort | identification of molecular determinants in irhoms1 and 2 that contribute to the substrate selectivity of stimulated adam17 |
| topic | ADAM17 (a disintegrin and metalloprotease 17) iRhom1 and 2 (inactive rhomboid like protein 1 and 2) EGFR-ligand (epidermal growth factor receptor ligand) protein ectodomain shedding |
| url | https://www.mdpi.com/1422-0067/23/21/12796 |
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