Caspase Substrates and Inhibitors

Poręba, Marcin; Stróżyk, Aleksandra; Salvesen, Guy S.; Drąg, Marcin

doi:10.1101/cshperspect.a008680

Cited by 166 publications

(147 citation statements)

References 142 publications

(175 reference statements)

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“…Recent proteomics analyses have identified more than 1,000 caspase substrates, most of which are bystander cleavages (35). Among gain-of-function cleavages, that of kinases (ROCK1, protein kinase C, and Mst1) removes a regulatory or inhibitory domain, and the activated kinases regulate the apoptotic signaling pathway (36).…”

Section: Effect Of Mouse Bsg and Nptn On Endogenous Xkr8-mediated Ptdsermentioning

confidence: 99%

Xkr8 phospholipid scrambling complex in apoptotic phosphatidylserine exposure

Suzuki

Imanishi

Nagata

2016

Proc. Natl. Acad. Sci. U.S.A.

117

130

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Xk-related protein (Xkr) 8, a protein carrying 10 transmembrane regions, is essential for scrambling phospholipids during apoptosis. Here, we found Xkr8 as a complex with basigin (BSG) or neuroplastin (NPTN), type I membrane proteins in the Ig superfamily. In BSG −/− NPTN −/− cells, Xkr8 localized intracellularly, and the apoptosis stimuli failed to expose phosphatidylserine, indicating that BSG and NPTN chaperone Xkr8 to the plasma membrane to execute its scrambling activity. Mutational analyses of BSG showed that the atypical glutamic acid in the transmembrane region is required for BSG's association with Xkr8. In cells exposed to apoptotic signals, Xkr8 was cleaved at the C terminus and the Xkr8/BSG complex formed a higher-order complex, likely to be a heterotetramer consisting of two molecules of Xkr8 and two molecules of BSG or NPTN, suggesting that this cleavage causes the formation of a larger complex of Xkr8-BSG/NPTN for phospholipid scrambling.phospholipid scramblase | Xkr8 | chaperone | basigin | neuroplastin P hospholipids are asymmetrically distributed in plasma membranes by flippases that actively translocate phosphatidylserine (PtdSer) and phosphatidylethanolamine from the outer to inner leaflets of the membrane (1, 2). This asymmetrical distribution is disrupted in the activated platelets and apoptotic cells (3), in which the PtdSer exposed on the cell surface serves as a scaffold for blood clotting factors and as an "eat me" signal, respectively (4, 5). ATP11A and ATP11C, members of the P4-type ATPase family, act as flippases at the plasma membrane in most cells (6, 7). Two processes, flippase inactivation and scramblase activation, must occur to disrupt the asymmetrical phospholipid distribution and expose PtdSer on the cell surface (8).Scramblases are membrane proteins that nonspecifically and bidirectionally transport phospholipids between the two plasma membrane leaflets (9). Ca 2+ -activated phospholipid scrambling is mediated by membrane proteins that belong to the transmembrane protein (TMEM)16 (also called ANO) family (8). Of 10 human TMEM16-family members, 5 are Ca 2+ -activated phospholipid scramblases at plasma membranes. TMEM16F exposes PtdSer in activated platelets and osteoblasts (10-12). The tertiary structure of fungal TMEM16 and the biochemical characterization of mouse TMEM16 family members indicate that TMEM16 forms a homodimer that directly binds Ca 2+ (13).Phospholipid scrambling and PtdSer exposure in apoptotic cells is mediated by another family of membrane proteins, the XK-related (Xkr) proteins (8). Of 10 human Xkr family members, Xkr8 (ubiquitously expressed) and Xkr4 and Xkr9 (expressed in specific tissues) are cleaved by caspase during apoptosis to expose PtdSer (14, 15), but how the cleavage activates these Xkrs to scramble phospholipids is unknown. XK, the founding member of the Xkr family, associates with Kell, a type II membrane protein (16). Whether Xkr8 and other Xkr-family members associate with other proteins has not been addressed.In this report, we found that...

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Section: Effect Of Mouse Bsg and Nptn On Endogenous Xkr8-mediated Ptdsermentioning

confidence: 99%

Xkr8 phospholipid scrambling complex in apoptotic phosphatidylserine exposure

Suzuki

Imanishi

Nagata

2016

Proc. Natl. Acad. Sci. U.S.A.

117

130

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“…Although many individual caspase substrates have been implicated in specific aspects of cellular destruction (e.g., lamin cleavage is required for the efficient packaging of nuclei into small membrane-bound vesicles), recent proteomic approaches have greatly expanded the known repertoire of proteolytic products generated during apoptosis (Van Damme et al 2005;Dix et al 2008;Mahrus et al 2008). Further work will be needed to confirm these findings and to determine how (or if ) all of these substrates participate in the apoptotic process (see Poreba et al 2013), especially as new details emerge on the relationship between posttranslational modifications, like phosphorylation, and caspase cleavage (Dix et al 2012).…”

mentioning

confidence: 99%

Cellular Mechanisms Controlling Caspase Activation and Function

Parrish

Freel

Kornbluth

2013

Cold Spring Harbor Perspectives in Biology

513

367

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Caspases are the primary drivers of apoptotic cell death, cleaving cellular proteins that are critical for dismantling the dying cell. Initially translated as inactive zymogenic precursors, caspases are activated in response to a variety of cell death stimuli. In addition to factors required for their direct activation (e.g., dimerizing adaptor proteins in the case of initiator caspases that lie at the apex of apoptotic signaling cascades), caspases are regulated by a variety of cellular factors in a myriad of physiological and pathological settings. For example, caspases may be modified posttranslationally (e.g., by phosphorylation or ubiquitylation) or through interaction of modulatory factors with either the zymogenic or active form of a caspase, altering its activation and/or activity. These regulatory events may inhibit or enhance enzymatic activity or may affect activity toward particular cellular substrates. Finally, there is emerging literature to suggest that caspases can participate in a variety of cellular processes unrelated to apoptotic cell death. In these settings, it is particularly important that caspases are maintained under stringent control to avoid inadvertent cell death. It is likely that continued examination of these processes will reveal new mechanisms of caspase regulation with implications well beyond control of apoptotic cell death.

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“…The apoptotic process is somewhat hierarchical and caspases can be assigned as initiators (2,8,9, and 10) and executioners (3,6, and 7). [1][2][3] Apoptosis can be triggered extrinsically via ligation of a death receptor by its cognate ligands, leading to the activation of caspases 8 and 10, or intrinsically following the release of cytochrome c from mitochondria with formation of a caspase 9 activation complex known as the apoptosome.…”

mentioning

confidence: 99%

“…2,[8][9][10][11] Unfortunately, most of them lack selectivity and cannot be used for selectively targeting or analyzing particular enzymes in complex biological environments. [12][13][14][15] This is entirely because of the overlapping specificities of the caspases on their preferred natural amino acid sequences.…”

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confidence: 99%

Unnatural amino acids increase sensitivity and provide for the design of highly selective caspase substrates

et al. 2014

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Traditional combinatorial peptidyl substrate library approaches generally utilize natural amino acids, limiting the usefulness of this tool in generating selective substrates for proteases that share similar substrate specificity profiles. To address this limitation, we synthesized a Hybrid Combinatorial Substrate Library (HyCoSuL) with the general formula of Ac-P4-P3-P2-Asp-ACC, testing the approach on a family of closely related proteases -the human caspases. The power of this library for caspase discrimination extends far beyond traditional PS-SCL approach, as in addition to 19 natural amino acids we also used 110 diverse unnatural amino acids that can more extensively explore the chemical space represented by caspase-active sites. Using this approach we identified and employed peptide-based substrates that provided excellent discrimination between individual caspases, allowing us to simultaneously resolve the individual contribution of the apical caspase-9 and the executioner caspase-3 and caspase-7 in the development of cytochrome-c-dependent apoptosis for the first time.

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Caspase Substrates and Inhibitors

Cited by 166 publications

References 142 publications

Xkr8 phospholipid scrambling complex in apoptotic phosphatidylserine exposure

Xkr8 phospholipid scrambling complex in apoptotic phosphatidylserine exposure

Cellular Mechanisms Controlling Caspase Activation and Function

Unnatural amino acids increase sensitivity and provide for the design of highly selective caspase substrates

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