title: Structural modeling defines transmembrane residues in ADAM17 that are crucial for Rhbdf2-ADAM17-dependent proteolysis.
abstract: A disintegrin and metalloproteinase 17 (ADAM17) controls the release of the pro-inflammatory cytokine tumor necrosis factor α (TNFα, also known as TNF) and is crucial for protecting the skin and intestinal barrier by proteolytic activation of epidermal growth factor receptor (EGFR) ligands. The seven-membrane-spanning protein called inactive rhomboid 2 (Rhbdf2; also known as iRhom2) is required for ADAM17-dependent TNFα shedding and crosstalk with the EGFR, and a point mutation (known as sinecure, sin) in the first transmembrane domain (TMD) of Rhbdf2 (Rhbdf2sin) blocks TNFα shedding, yet little is known about the underlying mechanism. Here, we used a structure-function analysis informed by structural modeling to evaluate the interaction between the TMD of ADAM17 and the first TMD of Rhbdf2, and the role of this interaction in Rhbdf2-ADAM17-dependent shedding. Moreover, we show that double mutant mice that are homozygous forRhbdf2sin/sinand lackRhbdf1closely resembleRhbdf1/2-/-double knockout mice, highlighting the severe functional impact of theRhbdf2sin/sinmutation on ADAM17 during mouse development. Taken together, these findings provide new mechanistic and conceptual insights into the critical role of the TMDs of ADAM17 and Rhbdf2 in the regulation of the ADAM17 and EGFR, and ADAM17 and TNFα signaling pathways.
authors.affiliation: Arthritis and Tissue Degeneration Program, Hospital for Special Surgery, New York, NY 10021, USA.|Dept. of Biochemistry, Cellular and Molecular Biology, Weill Cornell Medicine, New York, NY 10021, USA.
authors.forename: Xue
authors.initials: X
authors.lastname: Li
authors.affiliation: Arthritis and Tissue Degeneration Program, Hospital for Special Surgery, New York, NY 10021, USA.
authors.forename: Thorsten
authors.initials: T
authors.lastname: Maretzky
authors.affiliation: Department of Physiology, Biophysics and Systems Biology, Weill Cornell Medicine, New York, NY 10021, USA.|IBM Thomas J. Watson Research Center, Yorktown Heights, New York, NY 10598, USA.
authors.forename: Jose Manuel
authors.initials: JM
authors.lastname: Perez-Aguilar
authors.affiliation: Tri-Institutional Laboratory of Comparative Pathology, Sloan-Kettering Institute, New York, NY 10021 USA.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Monette
authors.affiliation: Arthritis and Tissue Degeneration Program, Hospital for Special Surgery, New York, NY 10021, USA.
authors.forename: Gisela
authors.initials: G
authors.lastname: Weskamp
authors.affiliation: Arthritis and Tissue Degeneration Program, Hospital for Special Surgery, New York, NY 10021, USA.
authors.forename: Sylvain
authors.initials: S
authors.lastname: Le Gall
authors.affiliation: Center for the Genetics of Host Defense, UT Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Bruce
authors.initials: B
authors.lastname: Beutler
authors.affiliation: Department of Physiology, Biophysics and Systems Biology, Weill Cornell Medicine, New York, NY 10021, USA.
authors.forename: Harel
authors.initials: H
authors.lastname: Weinstein
authors.affiliation: Arthritis and Tissue Degeneration Program, Hospital for Special Surgery, New York, NY 10021, USA blobelc@hss.edu.|Dept. of Biochemistry, Cellular and Molecular Biology, Weill Cornell Medicine, New York, NY 10021, USA.|Department of Physiology, Biophysics and Systems Biology, Weill Cornell Medicine, New York, NY 10021, USA.|Institute for Advanced Study, Technical University Munich, Garching 85748, Germany.
authors.forename: Carl P
authors.identifier: 0000-0001-5053-3137
authors.initials: CP
authors.lastname: Blobel
mesh_terms: D000072198:ADAM17 Protein / Q000737:chemistry* / Q000378:metabolism*; D000595:Amino Acid Sequence; D000596:Amino Acids / Q000378:metabolism; D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology; D002352:Carrier Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism; D004622:Embryo, Mammalian / Q000166:cytology; D005347:Fibroblasts / Q000378:metabolism; D006132:Growth Plate / Q000378:metabolism; D006351:Heart Valves / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D050505:Mutant Proteins / Q000737:chemistry / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D011485:Protein Binding; D059748:Proteolysis; D013329:Structure-Activity Relationship
chemical_list: D000596:Amino Acids; D002352:Carrier Proteins; D050505:Mutant Proteins; C569468:iRhom2 protein, mouse; D000072198:ADAM17 Protein
keywords: ADAM17; EGF receptor; Rhbdf2; TACE; iRhom2