Alternative Cleavage of Alzheimer-Associated Presenilins During Apoptosis by a Caspase-3 Family Protease

Kim, Tae‐Wan; Pettingell, Warren H.; Jung, Yong‐Keun; Kovacs, Dora M.; Tanzi, Rudolph E.

doi:10.1126/science.277.5324.373

Cited by 340 publications

(220 citation statements)

References 33 publications

(3 reference statements)

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“…Caspase family members play critical roles in neurodegenerative diseases (Kim et al, 1997;Canu et al, 1998;Kitamura et al, 1998;Gervais et al, 1999;Schultz et al, 1999). For example, Alzheimer's disease is a neurodegenerative disorder in which the neuronal cytoskeleton is progressively disrupted and displaced by PHF and in which altered caspase activity is implicated in mediating abnormal neuronal cell death Selznick et al, 1999).…”

Section: Discussionmentioning

confidence: 99%

Proapoptotic Effects of Tau Cleavage Product Generated by Caspase-3

Chung

Kim

et al. 2001

Neurobiology of Disease

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192

170

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Section: Discussionmentioning

confidence: 99%

Proapoptotic Effects of Tau Cleavage Product Generated by Caspase-3

Chung

Kim

et al. 2001

Neurobiology of Disease

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192

170

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“…2C, lanes 12-14). The 38-kDa band may represent a cleaved product by the caspase family, because its level was induced after treatment with staurosporine (not shown), an activator of caspases (41,42). Other bands are likely to be degrading intermediates by proteasome, since amounts of those bands greatly increased by treatment with lactacystin (data not shown), which is a potent inhibitor of proteasome.…”

Section: Endoproteolytic Cleavage and Pathological Function Of Ps2mentioning

confidence: 99%

Mutational Analysis of Intrinsic Regions of Presenilin 2 That Determine Its Endoproteolytic Cleavage and Pathological Function

Shirotani¹,

Takahashi²,

Araki³

et al. 2000

Journal of Biological Chemistry

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To investigate the significance of endoproteolytic processing of presenilin 2 (PS2) on its pathological function, we constructed PS2 cDNAs causing amino acid substitutions or deletions around the cleavage site. We found that a PS2 mutant (Del3) with a 20-amino acid deletion was not endoproteolytically processed, while other PS2s with amino acid substitutions and short deletions were cleaved. Overproduction of all the mutant proteins led to a compensatory decrease of endogenous PS1 fragments, but did not affect the amyloid ␤ peptide X-42/A␤ X-40 ratio without the familial Alzheimer's disease mutation. The Del3 mutant did not exhibit significant deficits in ␥-secretase activity. The turnover rate of the Del3 holoprotein was the same as that of full-length PS2. These data suggest that the determinants of the PS2 cleavage site reside within a large region and that the pathological function of PS2 is exerted by familial Alzheimer's disease mutations not related to the cleavage of holoproteins. We also found that PS2 with an 18-amino acid deletion at the C-terminal end was not processed. Its overexpression led neither to diminished accumulation of endogenous PS1 fragments nor to increased production of amyloid ␤ peptide X-42. The Cterminal end of PS2 seems to possess the signal for entry into the processing pathway.Mutations in homologous presenilin 1 and 2 (PS1 1 and PS2) genes are associated with early-onset autosomal dominant familial Alzheimer's disease (FAD) (1-3). To date, more than 50 different pathogenic missense mutations and one splice site mutation (loss of exon 10, designated as PS1⌬E10) have been found in PS1, and two missense mutations have been identified in PS2. The gene products of PS1 and PS2 are thought to contain six or eight transmembrane (TM) domains, and the N and C termini and a large hydrophilic loop region following the sixth TM domain are located within the cytoplasm (4 -6). PS1 proteins are involved in cell fate decisions by facilitating Notch signaling pathway (7-9). Recently, PS1 proteins have been shown to have a role in the endoproteolytic processing of ␤-amyloid precursor protein (APP) (10, 11) and , and trafficking of proteins including APP (15) and Notch (12, 13), while the physiological function of PS2 proteins is poorly understood. The amount of highly amyloidogenic A␤42 (amyloid ␤ peptide 42) increases in cells and transgenic mice with the PS1 and PS2 mutant genes (16 -20), supporting a hypothesis that mutations in PS lead to Alzheimer's disease by increasing the extracellular levels of A␤42.The PS proteins are proteolytically cleaved at the hydrophilic loop region and detected predominantly as N-terminal fragments (NTF) and C-terminal fragments (CTF) in culture cells and tissues (19,(21)(22)(23). The formation of PS fragments is highly regulated in a saturable and stoichiometric manner, since overproduction of full-length PS in transfected cells and transgenic mice does not yield a linear increase of fragments (21) and causes a compensatory decrease of the endogenous PS fragments...

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“…Given their pivotal role in the regulation of apoptosis, the caspases are important therapeutic targets, and it is evident that further investigation of caspase specificity and its relationship to structure is important for understanding cell death. A number of neurological diseases are connected to the caspase apoptotic pathway (19,20), and some small caspase inhibitors have been shown to block the effects of neuronal cell death (21)(22)(23)(24). A controlled activation of caspases, as desirable for cancer treatment, is more difficult to achieve.…”

mentioning

confidence: 99%

Crystal Structure of Caspase-2, Apical Initiator of the Intrinsic Apoptotic Pathway

Schweizer

Briand

Grütter

2003

Journal of Biological Chemistry

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The cell death protease caspase-2 has recently been recognized as the most apical caspase in the apoptotic cascade ignited during cell stress signaling. Cytotoxic stress, such as that caused by cancer therapies, leads to activation of caspase-2, which acts as a direct effector of the mitochondrion-dependent apoptotic pathway resulting in programmed cell death. Here we report the x-ray structure of caspase-2 in complex with the inhibitor acetyl-Leu-Asp-Glu-Ser-Asp-aldehyde at 1.65-Å resolution. Compared with other caspases, significant structural differences prevail in the active site region and the dimer interface. The structure reveals the hydrophobic properties of the S5 specificity pocket, which is unique to caspase-2, and provides the details of the inhibitorprotein interactions in subsites S1-S4. These features form the basis of caspase-2 specificity and allow the design of caspase-2-directed ligands for medical and analytical use. Another unique feature of caspase-2 is a disulfide bridge at the dimer interface, which covalently links the two monomers. Consistent with this finding, caspase-2 exists as a (p19/p12) 2 dimer in solution, even in the absence of substrates or inhibitors. The intersubunit disulfide bridge stabilizes the dimeric form of caspase-2, whereas all other long prodomain caspases exist as monomers in solution, and dimer formation is driven by ligand binding. Therefore, the central disulfide bridge appears to represent a novel way of dimer stabilization in caspases.

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Alternative Cleavage of Alzheimer-Associated Presenilins During Apoptosis by a Caspase-3 Family Protease

Cited by 340 publications

References 33 publications

Proapoptotic Effects of Tau Cleavage Product Generated by Caspase-3

Proapoptotic Effects of Tau Cleavage Product Generated by Caspase-3

Mutational Analysis of Intrinsic Regions of Presenilin 2 That Determine Its Endoproteolytic Cleavage and Pathological Function

Crystal Structure of Caspase-2, Apical Initiator of the Intrinsic Apoptotic Pathway

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