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At least 397 records · Page 22Linked to original sources
PubMed2004

Posttranslational modifications of tau--role in human tauopathies and modeling in transgenic animals.

Alzheimer's disease (AD) is characterized histopathologically by beta-amyloid-containing plaques, neurofibrillary tangles (NFT), reduced synaptic density, and neuronal loss in selected brain areas. Plaques consist of aggregates of a small peptide termed Abeta which is derived by proteolysis of the larger amyloid precursor protein APP, whereas NFT are composed of hyperphosphorylated forms of the microtubule-associated protein tau. Tau pathology in the presence of scant or no beta-amyloid plaques characterizes additional neurodegenerative disorders collectively called tauopathies. In the course of plaque and NFT formation, the major proteinaceous components of these lesions undergo post-translational modifications. In the case of tau, these include phosphorylation of mainly serine and threonine, but also tyrosine residues. In addition, tau is subject to ubiquitination, nitration, truncation, prolyl isomerization, association with heparan sulfate proteoglycan, glycosylation, glycation and modification by advanced glycation end-products (AGEs). This review aims to provide insight into the complexity of tau modifications in human tauopathies such as AD and frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17). Selected aspects of the post-translational modification of tau have been reproduced in transgenic animal models. Most of this work has been done in mice, but insight has also been gained from studies in the sea lamprey, the nematode C. elegans and Drosophila. Attempts have been made to link specific post-translational modifications with tau aggregation and nerve cell dysfunction.

Animals↗
PubMed2006

Posttranslational modifications of Bcl2 family members--a potential therapeutic target for human malignancy.

Apoptosis is a process that can occur normally, such as during tissue remodeling, embryogenesis or abnormally during certain pathologies, such as cancer. The identification of the Bcl2 as well as IAP family members has suggested that excessive inhibition of apoptosis may constitute a common feature of all known human cancers-the ability to influence their onset, progression and outcome. Bcl2 family proteins are frequently regulated by phosphorylation that affects their activity and conformation. The structural analysis of antiapoptotic members of Bcl2 family has contributed to a better understanding of the functional domains including the discovery of an unstructured "loop region" (LR) near the N-terminus exposed to the cytoplasm. The antiapoptotic members of Bcl2 family such as Bcl2/Bcl-xL/Mcl-1 are phosphorylated on specific serine/threonine residues within this unstructured loop in response to diverse stimuli including treatment with chemotherapeutic taxanes, survival factor addition or chemopreventive agents. In most instances, such phosphorylation has been associated with the loss of their biological function. The chemoresistant tumors overexpress Bcl2/Bcl-xL/Mcl-1. To this end, the apoptosis yielding effect due to phosphorylation of antiapoptotic Bcl2 family members is quite interesting. Phosphorylation-dephosphorylation pathway of these antiapoptotic proteins should be an ideal molecular target for therapy of subpopulation of cancer in which these death repressors are essential prognostic markers. Thus, further gaining the knowledge on the mechanism of inactivation of Bcl2/Bcl-xL/Mcl-1 by phosphorylation might be of paramount importance to therapy for human malignancies in which overexpression of these antiapoptotic proteins plays an essential role.

Alanine↗
PubMed1996

Posttranslational modification in rat bone osteopontin.

Osteopontin is a multiply-phosphorylated glycoprotein which contains an RGD cell adhesion sequence and regions containing a high level of aspartic acid. It is abundant in bone, milk, and urine and is also found in malignant tissues. Peptides generated from rat bone osteopontin by digestion with endoprotease Lys-C were analyzed for post-translational modification by a combination of Edman degradation and matrix-assisted laser desorption mass spectrometry. In the peptides analyzed in this way (accounting for approximately half the protein), eleven sites were found that were variably phosphorylated. Three modified lysines were also detected by virtue of their inability to be cleaved by endoprotease Lys-C (Lys19 and Lys286), by observation of an anomalous pth-amino acid during Edman degradation (Lys19 Lys29 and Lys286) and by a mass difference of 115 +/- 5. Bone osteopontin is extremely heterogeneous, as none of these modifications were found in 100% of peptides examined. In this respect, bone osteopontin differs from bovine milk osteopontin in which 28 residues are completely phosphorylated (Sørensen, et al., (1995) Protein Science 4:2040-2049). While the sequences of bovine and rat osteopontin differ significantly, many conserved serines in the N- and C-terminal regions that are phosphorylated in bovine milk osteopontin are at least partially phosphorylated in the rat bone protein. However, there are also conserved residues in both bovine and rat proteins which are phosphorylated in one species but not the other.

Amino Acid Sequence↗
PubMed1993

Posttranslational modification of beta 141 Leu associated with the beta 75(E19)Leu-->Pro mutation in Hb Atlanta.

The recent report of the oxidation of beta 141 Leu in a New Zealand family with Hb Atlanta [ beta 75(E19)Leu-->Pro] prompted us to reinvestigate the original Hb Atlanta case from Georgia. Tryptic peptide maps showed that the modified beta CoT-14 peptide was present together with beta AT-14 in isopropanol precipitates of Hb Atlanta. Amino acid analysis confirmed that beta CoT-14 lacked leucine and mass spectrometry indicated that it had an increased mass of 16 Daltons. These findings support the proposition that the beta 75 Leu-->Pro substitution in the E helix is the direct cause of the beta 141 Leu oxidation.

Amino Acid Sequence↗
PubMed1991

Axonal transport kinetics and posttranslational modification of synapsin I in mouse retinal ganglion cells.

Synapsin I is a neuron-specific phosphoprotein primarily localized at the presynaptic terminals, where it is thought to play an important role in the mechanisms involved in neurotransmitter release. Its interaction with cytoskeletal proteins and with small synaptic vesicles is regulated in vitro by phosphorylation by a calcium/calmodulin-dependent kinase. Here, we present the first evidence that, in the mouse retinal ganglion cells, synapsin I, moving along the axon with the slow component of axonal transport, is phosphorylated in vivo at both the head and tail regions. In addition, our data suggest that, after synapsin I has reached the nerve endings, the relative proportion of differently phosphorylated molecules of synapsin I changes, and that these changes lead to a decrease of the overall content of phosphorus. The more basic forms, here collectively referred to as beta-forms, become predominant at the terminals after 7 d postlabeling, when the bulk of transported synapsin I has entered the superior colliculus. Along the axon, phosphorylation could be functional in preventing synapsin I from forming, with actin, a dense meshwork that would restrict organelle movement. On the other hand, at the terminals, the dephosphorylation-phosphorylation of synapsin I may regulate the clustering of small synaptic vesicles and modulate neurotransmitter release by controlling the availability of small synaptic vesicles for exocytosis.

Animals↗
PubMed2006

Isothiocyanate iberin modulates phase II enzymes, posttranslational modification of histones and inhibits growth of Caco-2 cells by inducing apoptosis.

The aim of presented study was to further investigate the concentration-dependent changes induced by isothiocyanate iberin (IBN) in human colon carcinoma Caco-2 cells. The concentrations of IBN below IC(50) value (18 microM, 72 h) triggered the augmentation of mRNA levels for phase II detoxification GSTA1 and UGT1A1 enzymes and antioxidant thioredoxin reductase 1 gene in cells treated for 24 h. In addition a significant increase of acetylated H4 histone was detected. The mRNA induction peaked at IC(50) value and returned to level of control cells at 40 microM concentration of IBN. The cell cycle changes, gamma-H2AX stainability and the increase of phospho-H3 mitotic marker were induced at concentrations above IC(50) value. Appearance of Annexin V positive apoptotic cells and sub-G1 fragmented DNA as well as decrease of mitochondrial transmembrane potential confirmed cytotoxic effect of IBN observed in MTT assay. The predominance of necrotic cells and profound positivity of gamma-H2AX took place at the highest concentration of IBN. Thus, IBN represents the effective member of natural chemopreventive isothiocyanate family with which apoptotic potential can by employed to eliminate tumor cells.

Acetylation↗
PubMed1991

Posttranslational modifications of fibromodulin.

Tyrosine sulfate residues were identified in fibromodulin produced by tracheal chondrocytes, by tendon and sclera fibroblasts in primary culture, as well as in Chinese hamster ovary cells transfected with a construct containing fibromodulin cDNA. The tyrosine sulfate residues were located in the N-terminal part of fibromodulin. Thus, Chinese hamster ovary cells expressing a deleted variant of fibromodulin lacking the N-terminal 52 amino acids following the predicted signal peptide did not contain any tyrosine sulfate residues. The substitution with keratan sulfate chains was not restricted to chondrocytes, but was also identified in fibromodulin synthesized by bovine tendon fibroblasts and sclera fibroblasts, as well as in fibromodulin isolated from tendon. Digestion of fibromodulin with N-glycosidase F reduced the apparent size of fibromodulin to that of the core protein, as predicted from sequence analysis (Oldberg, A., Antonsson, P., Lindblom, K., and Heinegård, D. (1989) EMBO J.8, 2601-2604). Thus fibromodulin from cartilage, tendon, and sclera contains N-glycosidically linked oligosaccharides, some of which are extended to keratan sulfate chains.

Animals↗
PubMed1987

Posttranslational modification of neurofilament proteins by phosphate during axoplasmic transport in retinal ganglion cell neurons.

The progressive modification of newly synthesized neurofilament proteins (NFPs) during axoplasmic transport in mouse retinal ganglion cell (RGC) neurons was studied after RGC perikarya were pulse-labeled with 32P-orthophosphate or radiolabeled amino acids. The 3 NFP subunits, H(igh), M(iddle), and L(ow), were among a group of axonally transported proteins that incorporated high levels of 32P. Covalent addition of phosphate slowed the electrophoretic mobility of H and M on SDS polyacrylamide gels and shifted the charge of all 3 subunits toward more acidic pH values, thereby providing an index of the phosphorylation state of this radiolabeled population of NFPs. NFPs were extensively phosphorylated before they entered axons at the optic nerve level, and continued to be modified during transport along RGC axons at the optic nerve and tract level. H and M exhibited charge shifts of 0.2-0.6 units toward a more acidic pH during axoplasmic transport. The charge modifications became more prominent when NFPs reached distal axonal levels, which may indicate regional differences in the activity of this modification process along axons. By contrast, the L subunit became more basic in charge, consistent with decreases in the phosphorylation state during transport. Additional observations (Nixon and Lewis, 1986) that a considerable proportion of phosphate groups initially added to L and M were later removed as neurofilaments advanced along RGC axons support the notion that the changing phosphorylation state of NFP subunits during axoplasmic transport reflects a dynamic equilibrium between phosphorylation and dephosphorylation events. Topographical remodeling of phosphate groups on NFPs during axoplasmic transport is proposed as a possible mechanism for coordinating interactions between neurofilaments and other constituents, as these elements are transported and integrated into the axonal cytoskeleton.

Animals↗