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Structural and enzymatic insights into caspase-2 protein substrate recognition and catalysis.

Tang Y, Wells JA, Arkin MR
J Biol Chem 286 34147-54 (2011)
Related entries: 3r5j, 3r6g, 3r6l, 3r7n, 3r7s

Cited: 20 times
EuropePMC logo PMID: 21828056

Abstract

Caspase-2, the most evolutionarily conserved member in the human caspase family, may play important roles in stress-induced apoptosis, cell cycle regulation, and tumor suppression. In biochemical assays, caspase-2 uniquely prefers a pentapeptide (such as VDVAD) rather than a tetrapeptide, as required for efficient cleavage by other caspases. We investigated the molecular basis for pentapeptide specificity using peptide analog inhibitors and substrates that vary at the P5 position. We determined the crystal structures of apo caspase-2, caspase-2 in complex with peptide inhibitors VDVAD-CHO, ADVAD-CHO, and DVAD-CHO, and a T380A mutant of caspase-2 in complex with VDVAD-CHO. Two residues, Thr-380 and Tyr-420, are identified to be critical for the P5 residue recognition; mutation of the two residues reduces the catalytic efficiency by about 4- and 40-fold, respectively. The structures also provide a series of snapshots of caspase-2 in different catalytic states, shedding light on the mechanism of capase-2 activation, substrate binding, and catalysis. By comparing the apo and inhibited caspase-2 structures, we propose that the disruption of a non-conserved salt bridge between Glu-217 and the invariant Arg-378 is important for the activation of caspase-2. These findings broaden our understanding of caspase-2 substrate specificity and catalysis.

Reviews - 3r7b mentioned but not cited (1)

  1. Small Molecule Active Site Directed Tools for Studying Human Caspases. Poreba M, Szalek A, Kasperkiewicz P, Rut W, Salvesen GS, Drag M. Chem. Rev. 115 12546-12629 (2015)

Articles - 3r7b mentioned but not cited (2)

  1. Structural and enzymatic insights into caspase-2 protein substrate recognition and catalysis. Tang Y, Wells JA, Arkin MR. J. Biol. Chem. 286 34147-34154 (2011)
  2. Application of the Movable Type Free Energy Method to the Caspase-Inhibitor BindingAffinity Study. Xue S, Liu H, Zheng Z. Int J Mol Sci 20 E4850 (2019)


Reviews citing this publication (4)

  1. Caspase substrates and inhibitors. Poreba M, Strózyk A, Salvesen GS, Drag M. Cold Spring Harb Perspect Biol 5 a008680 (2013)
  2. Caspases and their substrates. Julien O, Wells JA. Cell Death Differ. 24 1380-1389 (2017)
  3. The p53-caspase-2 axis in the cell cycle and DNA damage response. Lim Y, Dorstyn L, Kumar S. Exp Mol Med 53 517-527 (2021)
  4. The Role of Caspase-2 in Regulating Cell Fate. Vigneswara V, Ahmed Z. Cells 9 (2020)

Articles citing this publication (13)

  1. miR-708 promotes the development of bladder carcinoma via direct repression of Caspase-2. Song T, Zhang X, Zhang L, Dong J, Cai W, Gao J, Hong B. J. Cancer Res. Clin. Oncol. 139 1189-1198 (2013)
  2. Mechanistic and structural understanding of uncompetitive inhibitors of caspase-6. Heise CE, Murray J, Augustyn KE, Bravo B, Chugha P, Cohen F, Giannetti AM, Gibbons P, Hannoush RN, Hearn BR, Jaishankar P, Ly CQ, Shah K, Stanger K, Steffek M, Tang Y, Zhao X, Lewcock JW, Renslo AR, Flygare J, Arkin MR. PLoS ONE 7 e50864 (2012)
  3. TRIM16 overexpression induces apoptosis through activation of caspase-2 in cancer cells. Kim PY, Rahmanto AS, Tan O, Norris MD, Haber M, Marshall GM, Cheung BB. Apoptosis 18 639-651 (2013)
  4. Analysis of the minimal specificity of caspase-2 and identification of Ac-VDTTD-AFC as a caspase-2-selective peptide substrate. Kitevska T, Roberts SJ, Pantaki-Eimany D, Boyd SE, Scott FL, Hawkins CJ. Biosci. Rep. 34 (2014)
  5. Enhancing the promiscuity of a member of the Caspase protease family by rational design. Öhlknecht C, Petrov D, Engele P, Kröß C, Sprenger B, Fischer A, Lingg N, Schneider R, Oostenbrink C. Proteins 88 1303-1318 (2020)
  6. Phosphorylation by Aurora B kinase regulates caspase-2 activity and function. Lim Y, De Bellis D, Sandow JJ, Capalbo L, D'Avino PP, Murphy JM, Webb AI, Dorstyn L, Kumar S. Cell Death Differ 28 349-366 (2021)
  7. Requirement for Serine-384 in Caspase-2 processing and activity. Zamaraev AV, Volik PI, Nilov DK, Turkina MV, Egorshina AY, Gorbunova AS, Iarovenko SI, Zhivotovsky B, Kopeina GS. Cell Death Dis 11 825 (2020)
  8. 14-3-3 protein masks the nuclear localization sequence of caspase-2. Smidova A, Alblova M, Kalabova D, Psenakova K, Rosulek M, Herman P, Obsil T, Obsilova V. FEBS J. 285 4196-4213 (2018)
  9. Bi-allelic truncating variants in CASP2 underlie a neurodevelopmental disorder with lissencephaly. Uctepe E, Vona B, Esen FN, Sonmez FM, Smol T, Tümer S, Mancılar H, Geylan Durgun DE, Boute O, Moghbeli M, Ghayoor Karimiani E, Hashemi N, Bakhshoodeh B, Kim HG, Maroofian R, Yesilyurt A. Eur J Hum Genet (2023)
  10. PROFICS: A bacterial selection system for directed evolution of proteases. Kröß C, Engele P, Sprenger B, Fischer A, Lingg N, Baier M, Öhlknecht C, Lier B, Oostenbrink C, Cserjan-Puschmann M, Striedner G, Jungbauer A, Schneider R. J Biol Chem 297 101095 (2021)
  11. Potent and selective caspase-2 inhibitor prevents MDM-2 cleavage in reversine-treated colon cancer cells. Poreba M, Rut W, Groborz K, Snipas SJ, Salvesen GS, Drag M. Cell Death Differ. 26 2695-2709 (2019)
  12. Resurrection of ancestral effector caspases identifies novel networks for evolution of substrate specificity. Grinshpon RD, Shrestha S, Titus-McQuillan J, Hamilton PT, Swartz PD, Clark AC. Biochem. J. 476 3475-3492 (2019)
  13. Structure-Based Design and Biological Evaluation of Novel Caspase-2 Inhibitors Based on the Peptide AcVDVAD-CHO and the Caspase-2-Mediated Tau Cleavage Sequence YKPVD314. Bresinsky M, Strasser JM, Vallaster B, Liu P, McCue WM, Fuller J, Hubmann A, Singh G, Nelson KM, Cuellar ME, Wilmot CM, Finzel BC, Ashe KH, Walters MA, Pockes S. ACS Pharmacol Transl Sci 5 20-40 (2022)


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