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Published March 4, 2014 | Supplemental Material + Published
Journal Article Open

Calpain-generated natural protein fragments as short-lived substrates of the N-end rule pathway


Calpains are Ca^(2+)-dependent intracellular proteases. We show here that calpain-generated natural C-terminal fragments of proteins that include G protein–coupled receptors, transmembrane ion channels, transcriptional regulators, apoptosis controllers, kinases, and phosphatases (Phe-GluN2a, Lys-Ica512, Arg-Ankrd2, Tyr-Grm1, Arg-Atp2b2, Glu-Bak, Arg-Igfbp2, Glu-IκBα, and Arg-c-Fos), are short-lived substrates of the Arg/N-end rule pathway, which targets destabilizing N-terminal residues. We also found that the identity of a fragment's N-terminal residue can change during evolution, but the residue's destabilizing activity is virtually always retained, suggesting selection pressures that favor a short half-life of the calpain-generated fragment. It is also shown that a self-cleavage of a calpain can result in an N-end rule substrate. Thus, the autoprocessing of calpains can control them by making active calpains short-lived. These and related results indicate that the Arg/N-end rule pathway mediates the remodeling of oligomeric complexes by eliminating protein fragments that are produced in these complexes through cleavages by calpains or other nonprocessive proteases. We suggest that this capability of the Arg/N-end rule pathway underlies a multitude of its previously known but mechanistically unclear functions.

Additional Information

© 2014 National Academy of Sciences. Contributed by Alexander Varshavsky, January 28, 2014 (sent for review January 18, 2014). Published ahead of print February 18, 2014. We thank E. Udartseva for excellent technical assistance; members of the A.V. laboratory for advice and help; and Brandon Wadas and Tri Vu for comments on the manuscript. This study was supported by National Institutes of Health Grants DK039520 and GM031530 (to A.V.). Author contributions: K.I.P., J.-H.O., and A.V. designed research; K.I.P., J.-H.O., and Y.L. performed research; K.I.P., J.-H.O., Y.L., and A.V. analyzed data; and K.I.P., J.-H.O., and A.V. wrote the paper. The authors declare no conflict of interest.

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Published - PNAS-2014-Piatkov-E817-26.pdf

Supplemental Material - SI.pdf


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