Proteins Polypeptide entries

Polypeptides are substrates for receptor-mediated transcytosis. Cerebral insulin reaches the brain from the circulation via receptor-mediated transcytosis through the BBB on the brain endothelial insulin receptor. This receptor is upregulated in development and downregulated in streptozotocin-induced diabetes mellitus. Similarly a BBB transferrin receptor mediates the transcytosis of transferrin across the BBB and this explains how the brain is able to extract iron from the circulation. Other RMT pathways consituting portals of entry to the brain for circulating peptides include receptors for insulin-like growth factors, cationic proteins, lectins, acetyl-low density lipoprotein and leptin. 

Figure 2 Structure of the 2 homodimeric Fe protein of A. vinelandii, with the subunits colored in light and dark gray. The polypeptide chains are shown in ribbon presentation, and the [4Fe-4S] cluster and the two bound MgADP are shown in space-filling representation. PDB entry 1FP6 and programs MOLSCRIPT and RASTERSwere used to generate this figure...

RNA secondary structure plays a role in the regulation of iron metabolism in eukaryotes. Iron is an essential nutrient, required for the synthesis of hemoglobin, cytochromes, and many other proteins. However, excess iron can be quite harmful because, untamed by a suitable protein environment, iron can initiate a range of free-radical reactions that damage proteins, lipids, and nucleic acids. Animals have evolved sophisticated systems for the accumulation of iron in times of scarcity and for the safe storage of excess iron for later use. Key proteins include transferrin, a transport protein that carries iron in the serum, transferrin receptor, a membrane protein that binds iron-loaded transferrin and initiates its entry into cells, and ferritin, an impressively efficient iron-storage protein found primarily in the liver and kidneys. Twenty-four ferritin polypeptides form a nearly spherical shell that encloses as many as 2400 iron atoms, a ratio of one iron atom per amino acid (Figure 31.37). 

The iron occurring in the iron storage protein ferritin can represent between 5 and 30% of the body s iroii. The exact value depends on a number of factors, including the dietary history of the individual. Ferritin has a molecular weight of 450,000 and contains 24 subunits, that is, 24 separate polypeptides. Each subunit forms a shell around a core of iron. The iron occurs as ferric iron (ferric hy-droxyphosphate). Iron enters lerritin as rcduccxl iron. The protein shell has 14 channels. It has been proposed that some of these channels are used for entry and exit of iron atoms. I he iron is oxidized within the interior of the protein shell to ferric iron. The mechanism responsible for this oxidation as iron enters ferritin, and for the reduction that occurs as iron leaves ferritin, is not clear. 

Endocytosis may not be required for the entry of an invasive adenylate cyclase from Bordello pertussis (Hanski and Ferfel, 1985 Donovan and Storm, 1990). This is a single chain protein (mol. wt. approx. 200 kDa) which resembles the edema factor from anthrax toxin in that it must interact with calmodulin to become active. In contrast to anthrax toxin, it consists of only one polypeptide which is, however, easily cleaved by proteases and thereby activated. An enzymatically active 45 kDa fragment is not active on whole cells, but it could in conjunction with the rest of the molecule enter the cytosol. The facts that this toxin acts much more rapidly than anthrax toxin, and that it is active even at 4 °C and on erythrocytes that have little, if any, endocytosis, suggest that the toxin is able to penetrate directly through the cell surface membrane. 

Malarial infection does not produce immunity in patients, and active research has been initiated to develop a malaria vaccine. " A vaccine that blocks the entry of sporozoites into the liver cells will prevent malaria at this stage. However, immunity to sporozoites does not protect the host against parasites in the erythrocytic cycle. Infective sporozoites of P. falciparum are covered by a polypeptide, circumsporozoite protein. Isolatiou aud ideutification of the gene encoding for this circumsporozoite protein have led to the development of a monoclonal antibody by recombinant DNA technology P. falciparum sporozoite vaccine is now under investigation. ... 

We also know of Ser/Thr-specific protein kinases that are an integral part of transmembrane receptors or of ion channels. The TGFyS-receptor contains a Ser/Thr-spe-cific protein kinase activity in the cytoplasmic part of its transmembrane polypeptide chain (see Chapter 12). Some members of a certain class of ion channels, named the transient receptor potential channels (TRP channels), carry a protein kinase activity on the cytoplasmic side of the channel protein that is essential for channel function. The TRP channels modulate Ca2+ entry into eukaryotic cells in response to external signals. The protein kinase activity is located on the cytoplasmic domain of the channel and can phosphorylate itself and other proteins on Ser/Thr residues (Runnels et ah, 2001). 

To allow for an access of two anchor groups to two identical or different active sites from the non-primed S subsites, the crystal structure of Ac-Leu-Leu-Nle-H bound to pS and pS of the yeast 20S proteasome was used as a template [34]. The entry of substrates into the proteolytic chamber is restricted by the bottle-neck of the a ring, which recruits from outside only fully unfolded linear polypeptides for digestion. This fact significantly restricts the choice of spacers for bivalent inhibitor constructs. Such a spacer should mimic as much as possible the unstructured polypeptide chain of an unfolded protein, and reach a length of about 50 A. Peptides of appropriate size are known to be rapidly degraded by the yeast proteasome, and thus linear polyoxyethylene (PEG) chains were selected as mimic of random-coiled polypeptide chains [37, 64], since this polymer is known to be highly solvated and... 

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