Protein storage granules

Figure 46-6. Flow of membrane proteins from the endoplasmic reticulum (ER) to the cell surface. Horizontal arrows denote steps that have been proposed to be signal independent and thus represent bulkflow. The open vertical arrows in the boxes denote retention of proteins that are resident in the membranes of the organelle indicated. The open vertical arrows outside the boxes indicate signal-mediated transport to lysosomes and secretory storage granules. (Reproduced, with permission, from Pfeffer SR, Rothman JE Biosynthetic protein transport and sorting by the endoplasmic reticulum and Golgi. Annu Rev Biochem 1987 56 829.)...

Mast Cells and Basophils. The chief sites of histamine storage are mast cells in the tissues and basophils in blood. These cells synthesize histamine and store it in secretory granules along with a heparin-protein complex. In response to specific antigens, mast cells or basophils are sensitized. Histamine is then secreted from the storage granules. Besides the histamine stores in mast cells and basophils, there is evidence of non-mast cell histamine in some tissues, particularly gastric and intestinal mucosa (60). 

Platelets support haemostasis in three ways first by sticking to exposed collagen to form a physical barrier at the site of vessel injury second by accelerating the activation of coagulation proteins and finally by release of storage granule contents promotes vasoconstriction and wound healing. 

Monoamines share the acid environment of the storage granule matrix with ATP, peptides, and proteins, the most well known of which are the chromogranins. The chro-mogranins are ubiquitous components of secretory vesicles and their widespread presence among endocrine tissue has led to their measurement in plasma as useful albeit relatively nonspecific markers of neuroendocrine tumors, including pheochromocytomas and carcinoid tumors. 

The main route of endocytosis is through the cla-thrin-mediated pathway. Specialized transient pits about 100 nm in diameter and coated by the structural protein dathrin can cover up to 2% of the cytosolic face of a plasma membrane. Roth and Porter first described these pits in 1964 as invaginations of the plasma membrane covered with bristle-like projections. The same bristles could be seen covering vesicles just inside the membrane deeper in the cell the vesicles had lost their bristles. They correcdy hypothesized that the bristle-coated pits invaginated to form coated vesicles, which then lost their coat and fused to form a storage granule. 

Chromaffin granules, platelet dense core vesicles, and synaptic vesicles accumulate ATP. ATP uptake has been demonstrated using chromaffin granules and synaptic vesicles and the process appears to depend on A(.lh+. It has generally been assumed that ATP is costored only with monoamines and acetylcholine, as an anion to balance to cationic charge of those transmitters. However, the extent of ATP storage and release by different neuronal populations remains unknown, and the proteins responsible for ATP uptake by secretory vesicles have not been identified. 

The recruitment of zinc for a structural role, or to activate an enzyme, has been observed. The zinc ion induces the dimerization of human growth hormone (hGH), with two Zn ions associated per dimer of hGH. This is confirmed by replacement of possible zinc binding residues resulting in weakened binding of the zinc ion. Formation of a zinc-hGH dimeric complex may be important for storage of hGH in secretory granules.975 In a toxic role, anthrax lethal factor is one of the three components of the secreted toxin and is a zinc-dependent protease that cleaves a protein kinase and causes lysis of macrophages.976... 

Finally, animal, plant and microbial tissues have been shown to contain the iron storage protein ferritin. The animal protein has been extensively studied, but the mechanism of iron binding has not been completely resolved (29). Animal tissues contain, in addition, a type of granule comprised of iron hydroxide, polysaccharide and protein. The latter, called hemosiderin, may represent a depository of excess iron (30). Interestingly, a protein with properties parallel to those of ferritin has been found in a mold. Here the function of the molecule can be examined with the powerful tools of biochemical genetics (31). 

A second form of storage iron is haemosiderin (Weir et al., 1984). This is deposited in humans as a response to the condition of iron overload. Haemosiderin forms as insoluble granules with electron dense cores surrounded by a protein shell. It exists in two forms primary haemosiderin is the result of iron overload due to excessive adsorption of iron in the gut, whereas the secondary form is caused by the numerous blood transfusions which are used to treat thallassaemia (a form of anaemia). Electron diffraction indicated that the iron core in primary haemosiderin is a 3-line ferrihydrite with magnetic hyperfine splitting only below 4 K and, in the secondary form, consists of poorly ordered goethite. As goethite is less soluble in ammonium oxalate buffer solution (pH 3) it has a lower intrinsic toxicity (Mann et al., 1988). 

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