A patient diagnosed with multiple myeloma, bicuspid aortic valve, and Von Hippel–Lindau syndrome underwent whole-exome sequencing seeking a unified genetic cause for these three pathologies. The patient possessed a single-point mutation of arginine to cysteine (R24C) in the N-terminal region(pro-domain) of matrix metalloproteinase 9 (MMP-9). The pro-domain interacts with the catalytic site of this enzyme rendering it inactive. MMP-9 has previously been associated with all three pathologies suffered by the patient. We hypothesized that the observed mutation in the pro-domain would influence the activity of this enzyme. We expressed recombinant versions of MMP-9 and an investigation of their biochemical properties revealed that MMP-9 R24C is a constitutively active zymogen. To our knowledge, this is the first example of a mutation that discloses catalytic activity in the pro-form in any of the 24 human MMPs.
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July 2022
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The cover image shows the double hexameric ring structures of Mycobacterium tuberculosis EccCb1 in apo and EsxAB+ATP+Mg2+ bound forms. The binding affinity EsxAB substrate to EccCb1 is enhanced ~2-fold in presence of ATP and Mg2+, which indicate the involvement of ATPase activity in EsxAB substrate translocation. Read more from Saxena and colleagues on pages 1559–1579
Research Article|
July 21 2022
Gain of function of a metalloproteinase associated with multiple myeloma, bicuspid aortic valve, and Von Hippel–Lindau syndrome
Scott J. Snipas
;
Scott J. Snipas
*
Resources, Data curation, Formal analysis, Supervision, Investigation, Methodology, Writing - original draft, Writing - review & editing
1Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, U.S.A.
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Roberto Jappelli;
Roberto Jappelli
*
Resources, Data curation, Formal analysis, Investigation, Visualization, Methodology, Writing - original draft
1Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, U.S.A.
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Ali Torkamani;
Ali Torkamani
Resources, Data curation, Formal analysis, Investigation, Visualization, Methodology, Writing - review & editing
2Scripps Research, La Jolla, CA, U.S.A.
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Giovanni Paternostro;
Giovanni Paternostro
Conceptualization, Resources, Data curation, Formal analysis, Supervision, Funding acquisition, Visualization, Methodology, Writing - original draft, Project administration
1Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, U.S.A.
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Guy S. Salvesen
Conceptualization, Resources, Formal analysis, Supervision, Funding acquisition, Validation, Investigation, Visualization, Methodology, Writing - original draft, Project administration, Writing - review & editing
1Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, U.S.A.
Correspondence: Guy S. Salvesen (gsalvesen@sbpdiscovery.org)
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Publisher: Portland Press Ltd
Received:
April 04 2022
Revision Received:
June 29 2022
Accepted:
July 04 2022
Accepted Manuscript online:
July 05 2022
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© 2022 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society
2022
Biochem J (2022) 479 (14): 1533–1542.
Article history
Received:
April 04 2022
Revision Received:
June 29 2022
Accepted:
July 04 2022
Accepted Manuscript online:
July 05 2022
Citation
Scott J. Snipas, Roberto Jappelli, Ali Torkamani, Giovanni Paternostro, Guy S. Salvesen; Gain of function of a metalloproteinase associated with multiple myeloma, bicuspid aortic valve, and Von Hippel–Lindau syndrome. Biochem J 29 July 2022; 479 (14): 1533–1542. doi: https://doi.org/10.1042/BCJ20220166
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