Peptidomics approach to elucidate the proteolytic regulation of bioactive peptides.

Proceedings of the National Academy of Sciences of the United States of America
Yun-Gon KimAlan Saghatelian

Abstract

Peptide hormones and neuropeptides have important roles in physiology and therefore the regulation of these bioactive peptides is of great interest. In some cases proteolysis controls the concentrations and signaling of bioactive peptides, and the peptidases that mediate this biochemistry have proven to be extremely successful drug targets. Due to the lack of any general method to identify these peptidases, however, the role of proteolysis in the regulation of most neuropeptides and peptide hormones is unknown. This limitation prompted us to develop an advanced peptidomics-based strategy to identify the peptidases responsible for the proteolysis of significant bioactive peptides. The application of this approach to calcitonin gene-related peptide (CGRP), a neuropeptide associated with blood pressure and migraine, revealed the endogenous CGRP cleavage sites. This information was then used to biochemically purify the peptidase capable of proteolysis of CGRP at those cleavage sites, which led to the identification of insulin-degrading enzyme (IDE) as a candidate CGRP-degrading enzyme. CGRP had not been identified as an IDE substrate before and we tested the physiological relevance of this interaction by quantitative measurements o...Continue Reading

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Citations

Aug 21, 2013·Nature Protocols·Yun-Gon KimAlan Saghatelian
Jul 31, 2013·PloS One·Andrew J MitchellAlan Saghatelian
Dec 15, 2015·Trends in Endocrinology and Metabolism : TEM·Wei-Jen Tang
Oct 20, 2015·Journal of Proteome Research·Takashi TsuchiyaKazuki Sasaki
Sep 23, 2014·Chemistry & Biology·Daniel Medina-Cleghorn, Daniel K Nomura
Jun 25, 2013·Current Opinion in Chemical Biology·Elena V RomanovaJonathan V Sweedler
Jan 22, 2013·Current Opinion in Chemical Biology·Anna Mari LoneAlan Saghatelian
Aug 8, 2013·Proceedings of the National Academy of Sciences of the United States of America·Lauren A McCordWei-Jen Tang
Dec 17, 2014·Journal of the American Chemical Society·Michaela ProthiwaAlan Saghatelian
Oct 8, 2014·Physiological Reviews·F A RussellS D Brain
Dec 24, 2018·Expert Review of Proteomics·Samantha Louise EdwardsLiliane Schoofs
Jul 18, 2019·Frontiers in Physiology·Ambrish KumarDonald J DiPette
Jul 17, 2021·Journal of Proteome Research·Rachel E ForemanRichard G Kay
Aug 28, 2018·Journal of Medicinal Chemistry·Dan YangZigang Li
Feb 11, 2020·Journal of Proteome Research·Laura A FleitesMichelle L Heck

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