Structural modeling defines transmembrane residues in ADAM17 that are crucial for Rhbdf2-ADAM17-dependent proteolysis

Xue Li; Thorsten Maretzky; Jose Manuel Perez-Aguilar; Sébastien Monette; Gisela Weskamp; Sylvain Le Gall; Bruce Beutler; Harel Weinstein; Carl P Blobel

doi:10.1242/jcs.196436

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Structural modeling defines transmembrane residues in ADAM17 that are crucial for Rhbdf2-ADAM17-dependent proteolysis

Journal article

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Peer reviewed

Structural modeling defines transmembrane residues in ADAM17 that are crucial for Rhbdf2-ADAM17-dependent proteolysis

Xue Li, Thorsten Maretzky, Jose Manuel Perez-Aguilar, Sébastien Monette, Gisela Weskamp, Sylvain Le Gall, Bruce Beutler, Harel Weinstein and Carl P Blobel

Journal of cell science, Vol.130(5), pp.868-878

03/01/2017

DOI: 10.1242/jcs.196436

PMCID: PMC5358332

PMID: 28104813

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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 (Rhbdf2 ) 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 for and lack closely resemble double knockout mice, highlighting the severe functional impact of the mutation 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.

Heart Valves - metabolism

Structure-Activity Relationship

ADAM17 Protein - metabolism

Amino Acids - metabolism

Mice, Mutant Strains

Proteolysis

Carrier Proteins - chemistry

Cell Membrane - metabolism

Fibroblasts - metabolism

ADAM17 Protein - chemistry

Amino Acid Sequence

Bone Marrow Cells - cytology

Mice, Inbred C57BL

Models, Molecular

Mutant Proteins - metabolism

Growth Plate - metabolism

Mutation - genetics

Molecular Dynamics Simulation

Carrier Proteins - genetics

Macrophages - metabolism

Animals

Carrier Proteins - metabolism

Embryo, Mammalian - cytology

Mutant Proteins - chemistry

Protein Binding

Molecular Docking Simulation

Details

Title: Subtitle: Structural modeling defines transmembrane residues in ADAM17 that are crucial for Rhbdf2-ADAM17-dependent proteolysis
Creators: Xue Li - Dept. of Biochemistry, Cellular and Molecular Biology, Weill Cornell Medicine, New York, NY 10021, USA
Thorsten Maretzky - Arthritis and Tissue Degeneration Program, Hospital for Special Surgery, New York, NY 10021, USA
Jose Manuel Perez-Aguilar - IBM Thomas J. Watson Research Center, Yorktown Heights, New York, NY 10598, USA
Sébastien Monette - Tri-Institutional Laboratory of Comparative Pathology, Sloan-Kettering Institute, New York, NY 10021 USA
Gisela Weskamp - Arthritis and Tissue Degeneration Program, Hospital for Special Surgery, New York, NY 10021, USA
Sylvain Le Gall - Arthritis and Tissue Degeneration Program, Hospital for Special Surgery, New York, NY 10021, USA
Bruce Beutler - Center for the Genetics of Host Defense, UT Southwestern Medical Center, Dallas, TX 75390, USA
Harel Weinstein - Department of Physiology, Biophysics and Systems Biology, Weill Cornell Medicine, New York, NY 10021, USA
Carl P Blobel - Institute for Advanced Study, Technical University Munich, Garching 85748, Germany
Resource Type: Journal article
Publication Details: Journal of cell science, Vol.130(5), pp.868-878
DOI: 10.1242/jcs.196436
PMID: 28104813
PMCID: PMC5358332
ISSN: 0021-9533
eISSN: 1477-9137
Grant note: R01 GM064750 / NIGMS NIH HHS U54 GM087519 / NIGMS NIH HHS P01 DA012408 / NIDA NIH HHS P30 CA008748 / NCI NIH HHS
Language: English
Date published: 03/01/2017
Academic Unit: Internal Medicine
Record Identifier: 9984094378002771

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