neuronal apoptosis

NAIP Protein, Human, Recombinant (His & SUMO) is expressed in E. coli.

Plays a role as a neuroprotective factor. Protects against neuronal cell death induced by multiple different familial Alzheimer disease genes and amyloid-beta proteins in Alzheimer disease. Mediates its neuroprotective effect by interacting with a receptor complex composed of IL6ST/GP130, IL27RA/WSX1 and CNTFR. Also acts as a ligand for G-protein coupled receptors FPR2/FPRL1 and FPR3/FPRL2. Inhibits amyloid-beta protein 40 fibril formation. Also inhibits amyloid-beta protein 42 fibril formation. Suppresses apoptosis by binding to BAX and preventing the translocation of BAX from the cytosol to mitochondria. Also suppresses apoptosis by binding to BID and inhibiting the interaction of BID with BAX and BAK which prevents oligomerization of BAX and BAK and suppresses release of apoptogenic proteins from mitochondria. Forms fibers with BAX and also with BID, inducing BAX and BID conformational changes and sequestering them into the fibers which prevents their activation. Can also suppress apoptosis by interacting with BIM isoform BimEL, inhibiting BimEL-induced activation of BAX, blocking oligomerization of BAX and BAK, and preventing release of apoptogenic proteins from mitochondria. Plays a role in up-regulation of anti-apoptotic protein BIRC6/APOLLON, leading to inhibition of neuronal cell death. Binds to IGFBP3 and specifically blocks IGFBP3-induced cell death. Competes with importin KPNB1 for binding to IGFBP3 which is likely to block IGFBP3 nuclear import. Induces chemotaxis of mononuclear phagocytes via FPR2/FPRL1. Reduces aggregation and fibrillary formation by suppressing the effect of APP on mononuclear phagocytes and acts by competitively inhibiting the access of FPR2 to APP. Protects retinal pigment epithelium (RPE) cells against oxidative stress-induced and endoplasmic reticulum (ER) stress-induced apoptosis. Promotes mitochondrial biogenesis in RPE cells following oxidative stress and promotes STAT3 phosphorylation which leads to inhibition of CASP3 release. Also reduces CASP4 levels in RPE cells, suppresses ER stress-induced mitochondrial superoxide production and plays a role in up-regulation of mitochondrial glutathione. Reduces testicular hormone deprivation-induced apoptosis of germ cells at the nonandrogen-sensitive stages of the seminiferous epithelium cycle. Protects endothelial cells against free fatty acid-induced inflammation by suppressing oxidative stress, reducing expression of TXNIP and inhibiting activation of the NLRP3 inflammasome which inhibits expression of proinflammatory cytokines IL1B and IL18. Protects against high glucose-induced endothelial cell dysfunction by mediating activation of ERK5 which leads to increased expression of transcription factor KLF2 and prevents monocyte adhesion to endothelial cells. Inhibits the inflammatory response in astrocytes. Increases the expression of PPARGC1A/PGC1A in pancreatic beta cells which promotes mitochondrial biogenesis. Increases insulin sensitivity.

Functions within a multiprotein E3 ubiquitin ligase complex, catalyzing the covalent attachment of ubiquitin moieties onto substrate proteins. Substrates include SYT11 and VDAC1. Other substrates are BCL2, CCNE1, GPR37, RHOT1/MIRO1, MFN1, MFN2, STUB1, SNCAIP, SEPTIN5, TOMM20, USP30, ZNF746, MIRO1 and AIMP2. Mediates monoubiquitination as well as 'Lys-6', 'Lys-11', 'Lys-48'-linked and 'Lys-63'-linked polyubiquitination of substrates depending on the context. Participates in the removal and/or detoxification of abnormally folded or damaged protein by mediating 'Lys-63'-linked polyubiquitination of misfolded proteins such as PARK7: 'Lys-63'-linked polyubiquitinated misfolded proteins are then recognized by HDAC6, leading to their recruitment to aggresomes, followed by degradation. Mediates 'Lys-63'-linked polyubiquitination of a 22 kDa O-linked glycosylated isoform of SNCAIP, possibly playing a role in Lewy-body formation. Mediates monoubiquitination of BCL2, thereby acting as a positive regulator of autophagy. Protects against mitochondrial dysfunction during cellular stress, by acting downstream of PINK1 to coordinate mitochondrial quality control mechanisms that remove and replace dysfunctional mitochondrial components. Depending on the severity of mitochondrial damage and/or dysfunction, activity ranges from preventing apoptosis and stimulating mitochondrial biogenesis to regulating mitochondrial dynamics and eliminating severely damaged mitochondria via mitophagy. Activation and recruitment onto the outer membrane of damaged/dysfunctional mitochondria (OMM) requires PINK1-mediated phosphorylation of both PRKN and ubiquitin. After mitochondrial damage, functions with PINK1 to mediate the decision between mitophagy or preventing apoptosis by inducing either the poly- or monoubiquitination of VDAC1, respectively; polyubiquitination of VDAC1 promotes mitophagy, while monoubiquitination of VDAC1 decreases mitochondrial calcium influx which ultimately inhibits apoptosis. When cellular stress results in irreversible mitochondrial damage, promotes the autophagic degradation of dysfunctional depolarized mitochondria (mitophagy) by promoting the ubiquitination of mitochondrial proteins such as TOMM20, RHOT1/MIRO1, MFN1 and USP30. Preferentially assembles 'Lys-6'-, 'Lys-11'- and 'Lys-63'-linked polyubiquitin chains, leading to mitophagy. The PINK1-PRKN pathway also promotes fission of damaged mitochondria by PINK1-mediated phosphorylation which promotes the PRKN-dependent degradation of mitochondrial proteins involved in fission such as MFN2. This prevents the refusion of unhealthy mitochondria with the mitochondrial network or initiates mitochondrial fragmentation facilitating their later engulfment by autophagosomes. Regulates motility of damaged mitochondria via the ubiquitination and subsequent degradation of MIRO1 and MIRO2; in motor neurons, this likely inhibits mitochondrial intracellular anterograde transport along the axons which probably increases the chance of the mitochondria undergoing mitophagy in the soma. Involved in mitochondrial biogenesis via the 'Lys-48'-linked polyubiquitination of transcriptional repressor ZNF746/PARIS which leads to its subsequent proteasomal degradation and allows activation of the transcription factor PPARGC1A. Limits the production of reactive oxygen species (ROS). Regulates cyclin-E during neuronal apoptosis. In collaboration with CHPF isoform 2, may enhance cell viability and protect cells from oxidative stress. Independently of its ubiquitin ligase activity, protects from apoptosis by the transcriptional repression of p53/TP53. May protect neurons against alpha synuclein toxicity, proteasomal dysfunction, GPR37 accumulation, and kainate-induced excitotoxicity. May play a role in controlling neurotransmitter trafficking at the presynaptic terminal and in calcium-dependent exocytosis. May represent a tumor suppressor gene.

Protein-glutamine gamma-glutamyltransferase 2, also known as Tissue transglutaminase, Transglutaminase C, Transglutaminase-2, and TGM2, is a member of the transglutaminase superfamily. TGM2 plays a role in cell growth and survival through the anti-apoptosis signaling pathway. It is a calcium-dependent acyltransferase that also undergoes a GTP-binding/GTPase cycle even though it lacks any obvious sequence similarity with canonical GTP-binding (G) proteins. TGM2 is a multi-functional protein which catalyzes transamidation reactions or acts as a G-protein in intracellular signalling. As an enzyme which is responsible for the majority of transglutaminase (TG) activity in the brain, TGM2 is likely to play a modulatory role in nervous system development and has regulatory effect on neuronal cell death as well. Most importantly, numerous studies have presented data demonstrating that dysregulation of TGM2 may contribute to the pathogenesis of many neurodegenerative disorders, including Huntington's disease, Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis as well as nervous system injuries.

Tumor necrosis factor receptor superfamily member 21(DR6) is a single-pass type I membrane protein and contains 1 death domain and 4 TNFR-Cys repeats. The protein may activate NF-kappa-B and promote apoptosis and it may activate JNK and be involved in T-cell differentiation.It is required for both normal cell body death and axonal pruning. Trophic-factor deprivation triggers the cleavage of surface APP by beta-secretase to release sAPP-beta which is further cleaved to release an N-terminal fragment of APP (N-APP). N-APP binds TNFRSF21 triggering caspase activation and degeneration of both neuronal cell bodies (via caspase-3) and axons (via caspase-6).

The precursor form of Brain-Derived Neurotrophic Factor (pro-BDNF) interacts preferentially with the pan-neurotrophin receptor p75 (p75NTR) and vps10p domain-containing receptor sortilin and induces neuronal apoptosis, whereas mature BDNF selectively binds with high affinity to the TrkB kinase receptor and promotes the survival, growth and differentiation of neurons. As proneurotrophins and mature neurotrophins elicit opposite biological effects, Pro-BDNF cleavage in the neuronal system is regulated in a specific and cell-context dependent manner. Pro-BDNF plays important role in negative regulation of neurotrophic actions in the brain.

Functions within a multiprotein E3 ubiquitin ligase complex, catalyzing the covalent attachment of ubiquitin moieties onto substrate proteins. Substrates include SYT11 and VDAC1. Other substrates are BCL2, CCNE1, GPR37, RHOT1/MIRO1, MFN1, MFN2, STUB1, SNCAIP, SEPTIN5, TOMM20, USP30, ZNF746, MIRO1 and AIMP2. Mediates monoubiquitination as well as 'Lys-6', 'Lys-11', 'Lys-48'-linked and 'Lys-63'-linked polyubiquitination of substrates depending on the context. Participates in the removal and/or detoxification of abnormally folded or damaged protein by mediating 'Lys-63'-linked polyubiquitination of misfolded proteins such as PARK7: 'Lys-63'-linked polyubiquitinated misfolded proteins are then recognized by HDAC6, leading to their recruitment to aggresomes, followed by degradation. Mediates 'Lys-63'-linked polyubiquitination of a 22 kDa O-linked glycosylated isoform of SNCAIP, possibly playing a role in Lewy-body formation. Mediates monoubiquitination of BCL2, thereby acting as a positive regulator of autophagy. Protects against mitochondrial dysfunction during cellular stress, by acting downstream of PINK1 to coordinate mitochondrial quality control mechanisms that remove and replace dysfunctional mitochondrial components. Depending on the severity of mitochondrial damage and/or dysfunction, activity ranges from preventing apoptosis and stimulating mitochondrial biogenesis to regulating mitochondrial dynamics and eliminating severely damaged mitochondria via mitophagy. Activation and recruitment onto the outer membrane of damaged/dysfunctional mitochondria (OMM) requires PINK1-mediated phosphorylation of both PRKN and ubiquitin. After mitochondrial damage, functions with PINK1 to mediate the decision between mitophagy or preventing apoptosis by inducing either the poly- or monoubiquitination of VDAC1, respectively; polyubiquitination of VDAC1 promotes mitophagy, while monoubiquitination of VDAC1 decreases mitochondrial calcium influx which ultimately inhibits apoptosis. When cellular stress results in irreversible mitochondrial damage, promotes the autophagic degradation of dysfunctional depolarized mitochondria (mitophagy) by promoting the ubiquitination of mitochondrial proteins such as TOMM20, RHOT1/MIRO1, MFN1 and USP30. Preferentially assembles 'Lys-6'-, 'Lys-11'- and 'Lys-63'-linked polyubiquitin chains, leading to mitophagy. The PINK1-PRKN pathway also promotes fission of damaged mitochondria by PINK1-mediated phosphorylation which promotes the PRKN-dependent degradation of mitochondrial proteins involved in fission such as MFN2. This prevents the refusion of unhealthy mitochondria with the mitochondrial network or initiates mitochondrial fragmentation facilitating their later engulfment by autophagosomes. Regulates motility of damaged mitochondria via the ubiquitination and subsequent degradation of MIRO1 and MIRO2; in motor neurons, this likely inhibits mitochondrial intracellular anterograde transport along the axons which probably increases the chance of the mitochondria undergoing mitophagy in the soma. Involved in mitochondrial biogenesis via the 'Lys-48'-linked polyubiquitination of transcriptional repressor ZNF746/PARIS which leads to its subsequent proteasomal degradation and allows activation of the transcription factor PPARGC1A. Limits the production of reactive oxygen species (ROS). Regulates cyclin-E during neuronal apoptosis. In collaboration with CHPF isoform 2, may enhance cell viability and protect cells from oxidative stress. Independently of its ubiquitin ligase activity, protects from apoptosis by the transcriptional repression of p53/TP53. May protect neurons against alpha synuclein toxicity, proteasomal dysfunction, GPR37 accumulation, and kainate-induced excitotoxicity. May play a role in controlling neurotransmitter trafficking at the presynaptic terminal and in calcium-dependent exocytosis. May represent a tumor suppressor gene.

The precursor form of the nerve growth factor (proNGF) like its mature form is characterized by the cystin knot motif consisting of three cystine bridges, whereas proneurotrophins and mature neurotrophins elicit opposite biological effects. ProNGF functions preferentially via the complex of pan-neurotrophin receptor p75 (p75NTR) and vps10p domain-containing receptor sortilin inducing neuronal apoptosis and contributing to age- and disease-related neurodegeneration.

Has DNA hydrolytic activity. Is capable of both single- and double-stranded DNA cleavage, producing DNA fragments with 3'-OH ends. Can cleave chromatin to nucleosomal units and cleaves nucleosomal and liposome-coated DNA. Acts in internucleosomal DNA fragmentation (INDF) during apoptosis and necrosis. The role in apoptosis includes myogenic and neuronal differentiation, and BCR-mediated clonal deletion of self-reactive B cells. Is active on chromatin in apoptotic cell-derived membrane-coated microparticles and thus suppresses anti-DNA autoimmunity. Together with DNASE1, plays a key role in degrading neutrophil extracellular traps (NETs). NETs are mainly composed of DNA fibers and are released by neutrophils to bind pathogens during inflammation. Degradation of intravascular NETs by DNASE1 and DNASE1L3 is required to prevent formation of clots that obstruct blood vessels and cause organ damage following inflammation.

Has DNA hydrolytic activity. Is capable of both single- and double-stranded DNA cleavage, producing DNA fragments with 3'-OH ends. Can cleave chromatin to nucleosomal units and cleaves nucleosomal and liposome-coated DNA. Acts in internucleosomal DNA fragmentation (INDF) during apoptosis and necrosis. The role in apoptosis includes myogenic and neuronal differentiation, and BCR-mediated clonal deletion of self-reactive B cells. Is active on chromatin in apoptotic cell-derived membrane-coated microparticles and thus suppresses anti-DNA autoimmunity. Together with DNASE1, plays a key role in degrading neutrophil extracellular traps (NETs). NETs are mainly composed of DNA fibers and are released by neutrophils to bind pathogens during inflammation. Degradation of intravascular NETs by DNASE1 and DNASE1L3 is required to prevent formation of clots that obstruct blood vessels and cause organ damage following inflammation.

Plays a central role in autophagy. Acts as core subunit of different PI3K complex forms that mediate formation of phosphatidylinositol 3-phosphate and are believed to play a role in multiple membrane trafficking pathways: PI3KC3-C1 is involved in initiation of autophagosomes and PI3KC3-C2 in maturation of autophagosomes and endocytosis. Involved in regulation of degradative endocytic trafficking and required for the abcission step in cytokinesis, probably in the context of PI3KC3-C2. Essential for the formation of PI3KC3-C2 but not PI3KC3-C1 PI3K complex forms. Involved in endocytosis including endosome formation in neuronal cells. May play a role in antiviral host defense.; Beclin-1-C 35 kDa localized to mitochondria can promote apoptosis; it induces the mitochondrial translocation of BAX and the release of proapoptotic factors.

MMP1, also known as MMP-1, contains 4 hemopexin-like domains and is a member of the matrix metalloproteinase (MMP) family. Matrix metalloproteases, also called matrixins, are zinc-dependent endopeptidases that are the major proteases involved in ECM degradation. MMPs are capable of degrading a wide range of extracellular molecules and some bioactive molecules. MMP activity is regulated by two major endogenous inhibitors: alpha2-macroglobulin and tissue inhibitors of metalloproteases (TIMPs). MMPs play a central role in cell proliferation, migration, differentiation, angiogenesis, apoptosis, and host defenses. Dysregulation of MMPs has been implicated in many diseases including arthritis, chronic ulcers, encephalomyelitis, and cancer. Tumour metastasis is a multistep process involving the dissemination of tumor cells from the primary tumor to secondary at a distant organ or tissue. One of the first steps in metastasis is the degradation of the basement membrane, a process in which MMPs have been implicated. MMPs are secreted by tumor cells themselves or by surrounding stromal cells stimulated by the nearby tumor. Numerous studies have linked altered MMP expression in different human cancers with poor disease prognosis. MMP-1, -2, -3, -7, -9, -13 and -14 all have elevated expression in primary tumors and/or metastases. MMP-1 cleaves collagens of types I, II, and III at one site in the helical domain. It also cleaves collagens of types VII and X. In case of HIV infection, MMP1 interacts and cleaves the secreted viral Tat protein, leading to a decrease in neuronal Tat's mediated neurotoxicity.

Has DNA hydrolytic activity. Is capable of both single- and double-stranded DNA cleavage, producing DNA fragments with 3'-OH ends. Can cleave chromatin to nucleosomal units and cleaves nucleosomal and liposome-coated DNA. Acts in internucleosomal DNA fragmentation (INDF) during apoptosis and necrosis. The role in apoptosis includes myogenic and neuronal differentiation, and BCR-mediated clonal deletion of self-reactive B cells. Is active on chromatin in apoptotic cell-derived membrane-coated microparticles and thus suppresses anti-DNA autoimmunity. Together with DNASE1, plays a key role in degrading neutrophil extracellular traps (NETs). NETs are mainly composed of DNA fibers and are released by neutrophils to bind pathogens during inflammation. Degradation of intravascular NETs by DNASE1 and DNASE1L3 is required to prevent formation of clots that obstruct blood vessels and cause organ damage following inflammation.

Plays a role as a neuroprotective factor. Protects against neuronal cell death induced by multiple different familial Alzheimer disease genes and amyloid-beta proteins in Alzheimer disease. Mediates its neuroprotective effect by interacting with a receptor complex composed of IL6ST/GP130, IL27RA/WSX1 and CNTFR. Also acts as a ligand for G-protein coupled receptors FPR2/FPRL1 and FPR3/FPRL2. Inhibits amyloid-beta protein 40 fibril formation. Also inhibits amyloid-beta protein 42 fibril formation. Suppresses apoptosis by binding to BAX and preventing the translocation of BAX from the cytosol to mitochondria. Also suppresses apoptosis by binding to BID and inhibiting the interaction of BID with BAX and BAK which prevents oligomerization of BAX and BAK and suppresses release of apoptogenic proteins from mitochondria. Forms fibers with BAX and also with BID, inducing BAX and BID conformational changes and sequestering them into the fibers which prevents their activation. Can also suppress apoptosis by interacting with BIM isoform BimEL, inhibiting BimEL-induced activation of BAX, blocking oligomerization of BAX and BAK, and preventing release of apoptogenic proteins from mitochondria. Plays a role in up-regulation of anti-apoptotic protein BIRC6/APOLLON, leading to inhibition of neuronal cell death. Binds to IGFBP3 and specifically blocks IGFBP3-induced cell death. Competes with importin KPNB1 for binding to IGFBP3 which is likely to block IGFBP3 nuclear import. Induces chemotaxis of mononuclear phagocytes via FPR2/FPRL1. Reduces aggregation and fibrillary formation by suppressing the effect of APP on mononuclear phagocytes and acts by competitively inhibiting the access of FPR2 to APP. Protects retinal pigment epithelium (RPE) cells against oxidative stress-induced and endoplasmic reticulum (ER) stress-induced apoptosis. Promotes mitochondrial biogenesis in RPE cells following oxidative stress and promotes STAT3 phosphorylation which leads to inhibition of CASP3 release. Also reduces CASP4 levels in RPE cells, suppresses ER stress-induced mitochondrial superoxide production and plays a role in up-regulation of mitochondrial glutathione. Reduces testicular hormone deprivation-induced apoptosis of germ cells at the nonandrogen-sensitive stages of the seminiferous epithelium cycle. Protects endothelial cells against free fatty acid-induced inflammation by suppressing oxidative stress, reducing expression of TXNIP and inhibiting activation of the NLRP3 inflammasome which inhibits expression of proinflammatory cytokines IL1B and IL18. Protects against high glucose-induced endothelial cell dysfunction by mediating activation of ERK5 which leads to increased expression of transcription factor KLF2 and prevents monocyte adhesion to endothelial cells. Inhibits the inflammatory response in astrocytes. Increases the expression of PPARGC1A/PGC1A in pancreatic beta cells which promotes mitochondrial biogenesis. Increases insulin sensitivity.

Calcium/calmodulin-dependent protein kinase II beta (CAMK2B) is a member of the serine/threonine protein kinase family and to the Ca(2+)/calmodulin-dependent protein kinase subfamily. CaMKII is an important player in prostate cancer cells ability to escape apoptosis under androgen ablation and facilitate the progression of prostate cancer cells to an androgen independent state. As a multifunctional protein kinase, the loss of activity may play a critical role in initiating the changes leading to ischemia-induced cell death. CaMKII are found to be important for the functions of immune cells. CaMKII can be activated by TLR ligands, and in turn promotes both myeloid differentiating factor 88 and Toll/IL-1 receptor domain-containing adaptor protein-inducing IFN-beta-dependent inflammatory responses by directly activating TAK1 and IRF3. CAMKII has four subunit isoforms (alpha, beta, gamma, delta). It is possible that distinct isoforms of this chain have different cellular localizations and interact differently with calmodulin. The alpha- and beta-isoforms have narrow distributions restricted mainly to neuronal tissues, but the gamma- and delta-isoforms are ubiquitously expressed within neuronal and non-neuronal tissues. CAMK2B is important for controlling the direction of plasticity at the parallel fiber-Purkinje cell synapse. CaMK2 is involved in neuronal survival through the reorganization of the neuroarchitecture and that the regulation of this role is controlled at the level of gene expression. Because CaMK2B influences the expression of many neuroreceptors and influences neural outgrowth and pruning, its altered expression in the cerebral cortex in schizophrenia or depression may contribute to schizophrenia and depression.