Journal article
The Functional Maturation of A Disintegrin and Metalloproteinase (ADAM) 9, 10, and 17 Requires Processing at a Newly Identified Proprotein Convertase (PC) Cleavage Site
The Journal of biological chemistry, Vol.290(19), pp.12135-12146
05/08/2015
DOI: 10.1074/jbc.M114.624072
PMCID: PMC4424348
PMID: 25795784
Abstract
Proenzyme maturation is a general mechanism to control the activation of enzymes. Catalytically active members of the A Disintegrin And Metalloprotease (ADAM) family of membrane-anchored metalloproteases are synthesized as proenzymes, in which the latency is maintained by their autoinhibitory pro-domains. A proteolytic processing then transforms the proenzyme into a catalytically active form. The removal of the pro-domain of ADAMs is currently thought to depend on processing at a canonical consensus site for the proprotein convertase Furin (RXXR) between the pro- and the catalytic domain. Here, we demonstrate that this previously described canonical site is a secondary cleavage site to a prerequisite cleavage in a newly characterized upstream PC site embedded within the pro-domain sequence. The novel upstream regulatory site is important for the maturation of several ADAM proenzymes. Mutations in the upstream regulatory site of ADAM17, ADAM10, and ADAM9 do not prevent pro-domain processing between the pro- and metalloprotease domain, but nevertheless, cause significantly reduced catalytic activity. Thus, our results have uncovered a novel functionally relevant PC processing site in the N-terminal part of the pro-domain that is important for the activation of these ADAMs. These results suggest that the novel PC site is part of a general mechanism underlying proenzyme maturation of ADAMs that is independent of processing at the previously identified canonical Furin cleavage site.
Background: Proprotein convertases (PCs) control the maturation of several A Disintegrin and Metalloprotease (ADAM) proteases.
Results: Mutating a newly identified upstream PC site interferes with activation of ADAMs 9, 10, and 17.
Conclusion: Processing at the upstream PC site is important for the activation of these ADAMs.
Significance: The upstream PC site in several ADAMs suggests a novel general mechanism for their maturation.
Details
- Title: Subtitle
- The Functional Maturation of A Disintegrin and Metalloproteinase (ADAM) 9, 10, and 17 Requires Processing at a Newly Identified Proprotein Convertase (PC) Cleavage Site
- Creators
- Eitan Wong - Department of Biological Regulation, Weizmann Institute of Science, Rehovot, 7610001, IsraelThorsten Maretzky - Arthritis and Tissue Degeneration Program, Hospital for Special Surgery, Biophysics and Systems Biology, Weill Cornell Medical College, New York, New York 10021Yoav Peleg - Israel Structural Proteomics Center, Weizmann Institute of Science, Rehovot, 7610001, IsraelCarl P Blobel - Arthritis and Tissue Degeneration Program, Hospital for Special Surgery, Biophysics and Systems Biology, Weill Cornell Medical College, New York, New York 10021Irit Sagi - Department of Biological Regulation, Weizmann Institute of Science, Rehovot, 7610001, Israel
- Resource Type
- Journal article
- Publication Details
- The Journal of biological chemistry, Vol.290(19), pp.12135-12146
- DOI
- 10.1074/jbc.M114.624072
- PMID
- 25795784
- PMCID
- PMC4424348
- NLM abbreviation
- J Biol Chem
- ISSN
- 0021-9258
- eISSN
- 1083-351X
- Publisher
- Elsevier Inc
- Grant note
- DOI: 10.13039/100000002, name: National Institutes of Health, award: GM64750
- Language
- English
- Date published
- 05/08/2015
- Academic Unit
- Internal Medicine
- Record Identifier
- 9984094309102771
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