systemic reaction characterized by fever, leukocytosis, increase in erythrocyte sedimentation rate, increases in Leucocytosis secretion of ACTH and glucocorticoids, activation of Complement activat complement and clotting cascades, decreases in serum levels of iron and zinc, a negative nitrogen balance, and by dramatic changes in the concentration of some plasma ,l' proteins. These proteins are named acute phase proteins. i

Interleukin-6 and the acute phase response

The heparan sulfate on the surface of all adherent cells modulates the actions of a large number of extracellular ligands. Members of both cell surface heparan sulfate proteoglycan families, the transmembrane syndecans and the glycosylphosphoinositide-linked glypicans, bind these ligands and enhance formation of their receptor-signaling complexes. These heparan sulfate proteoglycans also immobilize and regulate the turnover of ligands that act at the cell surface. The extracellular domains of these proteoglycans can be shed from the cell surface, generating soluble heparan sulfate proteoglycans that can inhibit interactions at the cell surface. Recent analyses of genetic defects in Drosophila melanogaster, mice, and humans confirm most of these activities in vivo and identify additional processes that involve cell surface heparan sulfate proteoglycans. This chapter focuses on the mechanisms underlying these activities and on the cellular functions that they regulate.

Functions of Cell Surface Heparan Sulfate Proteoglycans

Amyloid-beta peptide is central to the pathology of Alzheimer's disease, because it is neurotoxic--directly by inducing oxidant stress, and indirectly by activating microglia. A specific cell-surface acceptor site that could focus its effects on target cells has been postulated but not identified. Here we present evidence that the 'receptor for advanced glycation end products' (RAGE) is such a receptor, and that it mediates effects of the peptide on neurons and microglia. Increased expressing of RAGE in Alzheimer's disease brain indicates that it is relevant to the pathogenesis of neuronal dysfunction and death.

RAGE and amyloid-β peptide neurotoxicity in Alzheimer's disease

A knowledge base for predicting protein localization sites in eukaryotic cells

The progressive neurodegeneration of Alzheimer9s disease has been hypothesized to be mediated, at least in part, by beta-amyloid protein. A relationship between the aggregation state of beta-amyloid protein and its ability to promote degeneration in vitro has been previously suggested. To evaluate this hypothesis and to define a structure- activity relationship for beta-amyloid, aggregation properties of an overlapping series of synthetic beta-amyloid peptides (beta APs) were investigated and compared with beta AP neurotoxic properties in vitro. Using light microscopy, electrophoresis, and ultracentrifugation assays, we found that few beta APs assembled into aggregates immediately after solubilization, but that over time peptides containing the highly hydrophobic beta 29–35 region formed stable aggregations. In short-term neuronal cultures, toxicity was associated specifically with those beta APs that also exhibited significant aggregation. Further, upon the partial reversal of beta 1–42 aggregation, a concomitant loss of toxicity was observed. A synthetic peptide derived from a different amyloidogenic protein, islet amyloid polypeptide, exhibited aggregation but not toxicity, suggesting that beta AP-induced neurotoxicity in vitro is not a nonspecific reaction to aggregated protein. The correlation between beta AP aggregation and neurotoxicity was also observed in long-term neuronal cultures but not in astrocyte cultures. These data are consistent with the hypothesis that beta-amyloid protein contributes to neurodegeneration in Alzheimer9s disease.

https://www.jneurosci.org/content/jneuro/13/4/1676.full.pdf

Neurodegeneration induced by beta-amyloid peptides in vitro: the role of peptide assembly state

PERSPECTIVES AND SUMMARY 70 CHEMISTRY OF ACYL LINKAGES TO PROTEINS 71 BIOLOGY OF N-MYRISTOYLATION 73 Myristoylation of p60v-src. . . . . . . . . . . . . . . . . . . . . . .. . . . . . •. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . •. •. . . . . . . 74 M yristoylation Q{ Retrovirus Structura l Proteins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 76 N-Myristoylated Protein s Have Diff erent Intracellular Destinations. . . . . . . . . . . . . . . . . . . . 76 Regu lation o f Protein M yristoylation in Response to Hormonal Signa ls . . . . . . . . . . . . . . 78 MYRISTOYL COA: PROTEIN N-MYRISTOYL TRANSFERASE 78 An A ssay for NMT. . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ... . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . 79 Fatty Acid Sp ec ificity of NMT. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ........ 79 Yeast NMT P eptide Substrate Spec ificity. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 80 Importance of Sequ ence Context . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . 86 NMT in High er Eu karyotes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . 87 Identification of P otential N-Myristoylproteins from cDNA Data Bases . . . . . . . . . . . . . . . 88 ESTER-LINKED ACYLATION OF CELLULAR PROTEINS 88 M ye lin P roteolipid Proteins. . . . . . . . . . . . . . . . . . 90 Viral Glycoproteins. . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 90 Tran sferrin Receptor . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . .. . . . . . . . . 92 Mucus Glycoprotein s . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 92 The RAS Family of G Proteins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . .. . . . . . . . . . . . . . . . . 93 FUTURE DIRECTIONS 94

S P Adams

Papers

The biology and enzymology of eukaryotic protein acylation

Protein N-myristoylation

Amino-terminal processing of proteins by N-myristoylation. Substrate specificity of N-myristoyl transferase.

Myristoyl CoA:protein N-myristoyltransferase activities from rat liver and yeast possess overlapping yet distinct peptide substrate specificities.

Endocytosis and degradation of alpha 1-antitrypsin-protease complexes is mediated by the serpin-enzyme complex (SEC) receptor.