Structural Basis for Regulated Proteolysis by the α-Secretase ADAM10
Abstract
Cleavage of membrane-anchored proteins by ADAM (a disintegrin and metalloproteinase) endopeptidases plays a key role in a wide variety of biological signal transduction and protein turnover processes. Among ADAM family members, ADAM10 stands out as particularly important because it is both responsible for regulated proteolysis of Notch receptors and catalyzes the non-amyloidogenic α-secretase cleavage of the Alzheimer’s precursor protein (APP). We present here the X-ray crystal structure of the ADAM10 ectodomain, which, together with biochemical and cellular studies, reveals how access to the enzyme active site is regulated. Here, the enzyme adopts an unanticipated architecture in which the C-terminal cysteine-rich domain partially occludes the enzyme active site, preventing unfettered substrate access. Binding of a modulatory antibody to the cysteine-rich domain liberates the catalytic domain from autoinhibition, enhancing enzymatic activity toward a peptide substrate. Together, these studies reveal a mechanism for regulation of ADAM activity and offer a roadmap for its modulation.
- Authors:
- Publication Date:
- Research Org.:
- Argonne National Lab. (ANL), Argonne, IL (United States)
- Sponsoring Org.:
- USDOE Office of Science (SC), Basic Energy Sciences (BES). Scientific User Facilities Division; National Inst. of General Medical Sciences; National Inst. of Health
- OSTI Identifier:
- 1485750
- Alternate Identifier(s):
- OSTI ID: 1430341
- Grant/Contract Number:
- AC02-06CH11357; 5 R01 CA092433; 1 R35 CA220340; R01 NS038486; P41 GM103403
- Resource Type:
- Published Article
- Journal Name:
- Cell
- Additional Journal Information:
- Journal Name: Cell Journal Volume: 171 Journal Issue: 7; Journal ID: ISSN 0092-8674
- Publisher:
- Elsevier
- Country of Publication:
- United States
- Language:
- English
- Subject:
- 59 BASIC BIOLOGICAL SCIENCES; ADAM10; X-ray crystallography; amyloid precursor protein; Notch signaling
Citation Formats
Seegar, Tom C. M., Killingsworth, Lauren B., Saha, Nayanendu, Meyer, Peter A., Patra, Dhabaleswar, Zimmerman, Brandon, Janes, Peter W., Rubinstein, Eric, Nikolov, Dimitar B., Skiniotis, Georgios, Kruse, Andrew C., and Blacklow, Stephen C. Structural Basis for Regulated Proteolysis by the α-Secretase ADAM10. United States: N. p., 2017.
Web. doi:10.1016/j.cell.2017.11.014.
Seegar, Tom C. M., Killingsworth, Lauren B., Saha, Nayanendu, Meyer, Peter A., Patra, Dhabaleswar, Zimmerman, Brandon, Janes, Peter W., Rubinstein, Eric, Nikolov, Dimitar B., Skiniotis, Georgios, Kruse, Andrew C., & Blacklow, Stephen C. Structural Basis for Regulated Proteolysis by the α-Secretase ADAM10. United States. doi:10.1016/j.cell.2017.11.014.
Seegar, Tom C. M., Killingsworth, Lauren B., Saha, Nayanendu, Meyer, Peter A., Patra, Dhabaleswar, Zimmerman, Brandon, Janes, Peter W., Rubinstein, Eric, Nikolov, Dimitar B., Skiniotis, Georgios, Kruse, Andrew C., and Blacklow, Stephen C. Fri .
"Structural Basis for Regulated Proteolysis by the α-Secretase ADAM10". United States. doi:10.1016/j.cell.2017.11.014.
@article{osti_1485750,
title = {Structural Basis for Regulated Proteolysis by the α-Secretase ADAM10},
author = {Seegar, Tom C. M. and Killingsworth, Lauren B. and Saha, Nayanendu and Meyer, Peter A. and Patra, Dhabaleswar and Zimmerman, Brandon and Janes, Peter W. and Rubinstein, Eric and Nikolov, Dimitar B. and Skiniotis, Georgios and Kruse, Andrew C. and Blacklow, Stephen C.},
abstractNote = {Cleavage of membrane-anchored proteins by ADAM (a disintegrin and metalloproteinase) endopeptidases plays a key role in a wide variety of biological signal transduction and protein turnover processes. Among ADAM family members, ADAM10 stands out as particularly important because it is both responsible for regulated proteolysis of Notch receptors and catalyzes the non-amyloidogenic α-secretase cleavage of the Alzheimer’s precursor protein (APP). We present here the X-ray crystal structure of the ADAM10 ectodomain, which, together with biochemical and cellular studies, reveals how access to the enzyme active site is regulated. Here, the enzyme adopts an unanticipated architecture in which the C-terminal cysteine-rich domain partially occludes the enzyme active site, preventing unfettered substrate access. Binding of a modulatory antibody to the cysteine-rich domain liberates the catalytic domain from autoinhibition, enhancing enzymatic activity toward a peptide substrate. Together, these studies reveal a mechanism for regulation of ADAM activity and offer a roadmap for its modulation.},
doi = {10.1016/j.cell.2017.11.014},
journal = {Cell},
number = 7,
volume = 171,
place = {United States},
year = {2017},
month = {12}
}
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DOI: 10.1016/j.cell.2017.11.014
DOI: 10.1016/j.cell.2017.11.014
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