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Inhibitory mechanism of caspase-6 phosphorylation revealed by crystal structures, molecular dynamics simulations, and biochemical assays.

Cao Q, Wang XJ, Liu CW, Liu DF, Li LF, Gao YQ, Su XD
J Biol Chem 287 15371-9 (2012)
Cited: 19 times
EuropePMC logo PMID: 22433863

Abstract

The apoptotic effector caspase-6 (CASP6) has been clearly identified as a drug target due to its strong association with neurodegeneration and axonal pruning events as well as its crucial roles in Huntington disease and Alzheimer disease. CASP6 activity is suppressed by ARK5-mediated phosphorylation at Ser(257) with an unclear mechanism. In this work, we solved crystal structures of ΔproCASP6S257E and p20/p10S257E, which mimicked the phosphorylated CASP6 zymogen and activated CASP6, respectively. The structural investigation combined with extensive biochemical assay and molecular dynamics simulation studies revealed that phosphorylation on Ser(257) inhibited self-activation of CASP6 zymogen by "locking" the enzyme in the TEVD(193)-bound "inhibited state." The structural and biochemical results also showed that phosphorylation on Ser(257) inhibited the CASP6 activity by steric hindrance. These results disclosed the inhibition mechanism of CASP6 phosphorylation and laid the foundation for a new strategy of rational CASP6 drug design.

Articles - 3v6l mentioned but not cited (2)

  1. Inhibitory mechanism of caspase-6 phosphorylation revealed by crystal structures, molecular dynamics simulations, and biochemical assays. Cao Q, Wang XJ, Liu CW, Liu DF, Li LF, Gao YQ, Su XD. J Biol Chem 287 15371-15379 (2012)
  2. Activation of Caspase-6 Is Promoted by a Mutant Huntingtin Fragment and Blocked by an Allosteric Inhibitor Compound. Ehrnhoefer DE, Skotte NH, Reinshagen J, Qiu X, Windshügel B, Jaishankar P, Ladha S, Petina O, Khankischpur M, Nguyen YTN, Caron NS, Razeto A, Meyer Zu Rheda M, Deng Y, Huynh KT, Wittig I, Gribbon P, Renslo AR, Geffken D, Gul S, Hayden MR. Cell Chem Biol 26 1295-1305.e6 (2019)


Reviews citing this publication (6)

  1. Activation and regulation of caspase-6 and its role in neurodegenerative diseases. Wang XJ, Cao Q, Zhang Y, Su XD. Annu Rev Pharmacol Toxicol 55 553-572 (2015)
  2. Caspase-6 as a novel early target in the treatment of Alzheimer's disease. LeBlanc AC. Eur J Neurosci 37 2005-2018 (2013)
  3. Recent advances suggest increased influence of selective pressure in allostery. Bhat AS, Dustin Schaeffer R, Kinch L, Medvedev KE, Grishin NV. Curr Opin Struct Biol 62 183-188 (2020)
  4. Non-Canonical Roles of Apoptotic Caspases in the Nervous System. Dehkordi MH, Munn RGK, Fearnhead HO. Front Cell Dev Biol 10 840023 (2022)
  5. Role of ARK5 in cancer and other diseases (Review). Mo G, Zhang B, Jiang Q. Exp Ther Med 22 697 (2021)
  6. How does caspases regulation play role in cell decisions? apoptosis and beyond. Ghorbani N, Yaghubi R, Davoodi J, Pahlavan S. Mol Cell Biochem (2023)

Articles citing this publication (11)

  1. Structural snapshots reveal distinct mechanisms of procaspase-3 and -7 activation. Thomsen ND, Koerber JT, Wells JA. Proc Natl Acad Sci U S A 110 8477-8482 (2013)
  2. Alterations of myelin morphology and oligodendrocyte development in early stage of Alzheimer's disease mouse model. Wu Y, Ma Y, Liu Z, Geng Q, Chen Z, Zhang Y. Neurosci Lett 642 102-106 (2017)
  3. A multipronged approach for compiling a global map of allosteric regulation in the apoptotic caspases. Dagbay K, Eron SJ, Serrano BP, Velázquez-Delgado EM, Zhao Y, Lin D, Vaidya S, Hardy JA. Methods Enzymol 544 215-249 (2014)
  4. Tunable allosteric library of caspase-3 identifies coupling between conserved water molecules and conformational selection. Maciag JJ, Mackenzie SH, Tucker MB, Schipper JL, Swartz P, Clark AC. Proc Natl Acad Sci U S A 113 E6080-E6088 (2016)
  5. Modifying caspase-3 activity by altering allosteric networks. Cade C, Swartz P, MacKenzie SH, Clark AC. Biochemistry 53 7582-7595 (2014)
  6. Phosphorylation by protein kinase A disassembles the caspase-9 core. Serrano BP, Hardy JA. Cell Death Differ 25 1025-1039 (2018)
  7. Identification of Allosteric Inhibitors against Active Caspase-6. Tubeleviciute-Aydin A, Beautrait A, Lynham J, Sharma G, Gorelik A, Deny LJ, Soya N, Lukacs GL, Nagar B, Marinier A, LeBlanc AC. Sci Rep 9 5504 (2019)
  8. Rare human Caspase-6-R65W and Caspase-6-G66R variants identify a novel regulatory region of Caspase-6 activity. Tubeleviciute-Aydin A, Zhou L, Sharma G, Soni IV, Savinov SN, Hardy JA, LeBlanc AC. Sci Rep 8 4428 (2018)
  9. The regulatory mechanism of the caspase 6 pro-domain revealed by crystal structure and biochemical assays. Cao Q, Wang XJ, Li LF, Su XD. Acta Crystallogr D Biol Crystallogr 70 58-67 (2014)
  10. Computational study of the effects of protein tyrosine nitrations on the catalytic activity of human thymidylate synthase. Jarmuła A, Rode W. J Comput Aided Mol Des 27 45-66 (2013)
  11. Modulation of procaspase-7 self-activation by PEST amino acid residues of the N-terminal prodomain and intersubunit linker. Alves J, Garay-Malpartida M, Occhiucci JM, Belizário JE. Biochem Cell Biol 95 634-643 (2017)


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