Elizabeth J. Coulson

Inhibitor of apoptosis proteins and their relatives: IAPs and other BIRPs.

SummaryApoptosis is a physiological cell death process important for development, homeostasis and the immune defence of multicellular animals. The key effectors of apoptosis are caspases, cysteine proteases that cleave after aspartate residues. The inhibitor of apoptosis (IAP) family of proteins prevent cell death by binding to and inhibiting active caspases and are negatively regulated by IAP-binding proteins, such as the mammalian protein DIABLO/Smac. IAPs are characterized by the presence of one to three domains known as baculoviral IAP repeat (BIR) domains and many also have a RING-finger domain at their carboxyl terminus. More recently, a second group of BIR-domain-containing proteins (BIRPs) have been identified that includes the mammalian proteins Bruce and Survivin as well as BIR-containing proteins in yeasts and Caenorhabditis elegans. These Survivin-like BIRPs regulate cytokinesis and mitotic spindle formation. In this review, we describe the IAPs and other BIRPs, their evolutionary relationships and their subcellular and tissue localizations.

Conservation of baculovirus inhibitor of apoptosis repeat proteins (BIRPs) in viruses, nematodes, vertebrates and yeasts

Amino acid display was performed using the program ASAD developed by Keith Satterly, WEHI, and is available by anonymous ftp from: ftp.wehi.edu.au/pub/biology/ASAD. This work was supported by the Anti-Cancer Council of Victoria.

What the evolution of the amyloid protein precursor supergene family tells us about its function.

The Alzheimers disease amyloid protein precursor (APP) gene is part of a multi-gene super-family from which sixteen homologous amyloid precursor-like proteins (APLP) and APP species homologues have been isolated and characterised. Comparison of exon structure (including the uncharacterised APL-1 gene), construction of phylogenetic trees, and analysis of the protein sequence alignment of known homologues of the APP super-family were performed to reconstruct the evolution of the family and to assess the functional significance of conserved protein sequences between homologues. This analysis supports an adhesion function for all members of the APP super family, with specificity determined by those sequences which are not conserved between APLP lineages, and provides evidence for an increasingly complex APP superfamily during evolution. The analysis also suggests that Drosophila APPL and Caenorhabditis elegans APL-1 may be a fourth APLP lineage indicating that these proteins, while not functional homologues of human APP, are similarly likely to regulate cell adhesion. Furthermore, the betaA4 sequence is highly conserved only in APP orthologues, strongly suggesting this sequence is of significant functional importance in this lineage.

β-Amyloid1–42 Induces Neuronal Death through the p75 Neurotrophin Receptor

Alzheimers disease is characterized by the accumulation of neurotoxic amyloidogenic peptide Aβ, degeneration of the cholinergic innervation to the hippocampus (the septohippocampal pathway), and progressive impairment of cognitive function, particularly memory. Aβ is a ligand for the p75 neurotrophin receptor (p75NTR), which is best known for mediating neuronal death and has been consistently linked to the pathology of Alzheimers disease. Here we examined whether p75NTR is required for Aβ-mediated effects. Treatment of wild-type but not p75NTR-deficient embryonic mouse hippocampal neurons with human Aβ1–42 peptide induced significant cell death. Furthermore, injection of Aβ1–42 into the hippocampus of adult mice resulted in significant degeneration of wild-type but not p75NTR-deficient cholinergic basal forebrain neurons, indicating that the latter are resistant to Aβ-induced toxicity. We also found that neuronal death correlated with Aβ1–42 peptide-stimulated accumulation of the death-inducing p75NTR C-terminal fragment generated by extracellular metalloprotease cleavage of full-length p75NTR. Although neuronal death was prevented in the presence of the metalloprotease inhibitor TAPI-2 (tumor necrosis factor-α protease inhibitor-2), Aβ1–42-induced accumulation of the C-terminal fragment resulted from inhibition of γ-secretase activity. These results provide a novel mechanism to explain the early and characteristic loss of cholinergic neurons in the septohippocampal pathway that occurs in Alzheimers disease.

p75 Neurotrophin Receptor Expression Defines a Population of BDNF-Responsive Neurogenic Precursor Cells

Although our understanding of adult neurogenesis has increased dramatically over the last decade, confusion still exists regarding both the identity of the stem cell responsible for neuron production and the mechanisms that regulate its activity. Here we show, using flow cytometry, that a small population of cells (0.3%) within the stem cell niche of the rat subventricular zone (SVZ) expresses the p75 neurotrophin receptor (p75NTR) and that these cells are responsible for neuron production in both newborn and adult animals. In the adult, the p75NTR-positive population contains all of the neurosphere-producing precursor cells, whereas in the newborn many of the precursor cells are p75NTR negative. However, at both ages, only the neurospheres derived from p75NTR-positive cells are neurogenic. We also show that neuron production from p75NTR-positive but not p75NTR-negative precursors is greatly enhanced after treatment with brain-derived neurotrophic factor (BDNF) or nerve growth factor. This effect appears to be mediated specifically by p75NTR, because precursor cells from p75NTR-deficient mice show a 70% reduction in their neurogenic potential in vitro and fail to respond to BDNF treatment. Furthermore, adult p75NTR-deficient mice have significantly reduced numbers of PSA-NCAM (polysialylated neural cell adhesion molecule)-positive SVZ neuroblasts in vivo and a lower olfactory bulb weight. Thus, p75NTR defines a discrete population of highly proliferative SVZ precursor cells that are able to respond to neurotrophin activation by increasing neuroblast generation, making this pathway the most likely mechanism for the increased neurogenesis that accompanies raised BDNF levels in a variety of disease and behavioral situations.

Chopper, a New Death Domain of the p75 Neurotrophin Receptor That Mediates Rapid Neuronal Cell Death

The cytoplasmic juxtamembrane region of the p75 neurotrophin receptor (p75NTR) has been found to be necessary and sufficient to initiate neural cell death. The region was named “Chopper” to distinguish it from CD95-like death domains. A 29-amino acid peptide corresponding to the Chopper region induced caspase- and calpain-mediated death in a variety of neural and non-neural cell types and was not inhibited by signaling through Trk (unlike killing by full-length p75NTR). Chopper triggered cell death only when bound to the plasma membrane by a lipid anchor, whereas non-anchored Chopper acted in a dominant-negative manner, blocking p75NTR-mediated death both in vitroand in vivo. Removal of the ectodomain of p75NTR increased the potency of Chopper activity, suggesting that it regulates the association of Chopper with downstream signaling proteins.

Does the p75 neurotrophin receptor mediate Abeta-induced toxicity in Alzheimer's disease?

Alzheimers disease is characterized by the over‐production and accumulation of amyloidogenic Aβ peptide, which can induce cell death in vitro. It has been suggested that the death signal could be transduced by the pan neurotrophin receptor (p75NTR). p75NTR is well known for its ability to mediate neuronal death in neurodegenerative conditions and is inextricably linked with changes that occur in Alzheimers disease. Moreover, Aβ binds to p75NTR, activating signalling cascades. However, the complexity of p75NTR‐mediated signalling, which does not always promote cell death, leaves open the possibly of Aβ promoting death via an alternative signalling pathway or the regulation of other p75NTR‐mediated actions. This review focuses on the interactions between Aβ and p75NTR in the context of the broader p75NTR signalling field, and offers alternative explanations for how p75NTR might contribute to the aetiology of Alzheimers disease.

Proteolytic processing of the p75 neurotrophin receptor: A prerequisite for signalling?: Neuronal life, growth and death signalling are crucially regulated by intra-membrane proteolysis and trafficking of p75(NTR)

The common neurotrophin receptor (p75NTR) regulates various functions in the developing and adult nervous system. Cell survival, cell death, axonal and growth cone retraction, and regulation of the cell cycle can be regulated by p75NTR‐mediated signals following activation by either mature or pro‐neurotrophins and in combination with various co‐receptors, including Trk receptors and sortilin. Here, we review the known functions of p75NTR by cell type, receptor‐ligand combination, and whether regulated intra‐membrane proteolysis of p75NTR is required for signalling. We highlight that the generation of the intracellular domain fragment of p75NTR is associated with many of the receptor functions, regardless of its ligand and co‐receptor interactions.

Structural basis for endosomal trafficking of diverse transmembrane cargos by PX-FERM proteins.

Transit of proteins through the endosomal organelle following endocytosis is critical for regulating the homeostasis of cell-surface proteins and controlling signal transduction pathways. However, the mechanisms that control these membrane-transport processes are poorly understood. The Phox-homology (PX) domain-containing proteins sorting nexin (SNX) 17, SNX27, and SNX31 have emerged recently as key regulators of endosomal recycling and bind conserved Asn-Pro-Xaa-Tyr–sorting signals in transmembrane cargos via an atypical band, 4.1/ezrin/radixin/moesin (FERM) domain. Here we present the crystal structure of the SNX17 FERM domain bound to the sorting motif of the P-selectin adhesion protein, revealing both the architecture of the atypical FERM domain and the molecular basis for recognition of these essential sorting sequences. We further show that the PX-FERM proteins share a promiscuous ability to bind a wide array of putative cargo molecules, including receptor tyrosine kinases, and propose a model for their coordinated molecular interactions with membrane, cargo, and regulatory proteins.

Down-regulation of the amyloid protein precursor of Alzheimer's disease by antisense oligonucleotides reduces neuronal adhesion to specific substrata

The hallmark of Alzheimers disease is the cerebral deposition of amyloid which is derived from the amyloid precursor protein (APP). The function of APP is unknown but there is increasing evidence for the role of APP in cell-cell and/or cell-matrix interactions. Primary cultures of murine neurons were treated with antisense oligonucleotides to down-regulate APP. This paper presents evidence that APP mediates a substrate-specific interaction between neurons and extracellular matrix components collagen type I, laminin and heparan sulphate proteoglycan but not fibronectin or poly-L-lysine. It remains to be determined whether this effect is the direct result of APP-matrix interactions, or whether an intermediatry pathway is involved.