Nexin

Protease nexin (From cultured human fibroblasts) [148263-58-5], Purified by affinity binding of protease nexin to dextran sulfate-Sepharose. [Farrell et al. Biochem J 237 707 1986.]... 

FIGURE 17.5 The structure of an axoneme. Note the manner in which two microtubules are joined in the nine outer pairs. The smaller-diameter tubule of each pair, which is a true cylinder, is called the A-tubule and isjoined to the center sheath of the axoneme by a spoke structure. Each outer pair of tubules isjoined to adjacent pairs by a nexin bridge. The A-tubule of each outer pair possesses an outer dynein arm and an inner dynein arm. The larger-diameter tubule is known as the B-tubule. 

Other lateral structures that are bound to the microtubules of cilia and flagella are filamentous interdoublet links composed of nexin, radial spokes directed to the central pair of microtubules, and a central sheath that is attached to the walls of the central pair (Figure 1). 

An isolated flagellum will continue to bend actively, indicating that this function is linked to its intrinsic structure. Treatment of cilia from the protozoan Tetra-hymena with the proteolytic enzyme trypsin selectively dissolves the nexin links and radial spokes but leaves unaffected the microtubules and dynein arms. If such a preparation is treated with a small amount of ATP, the loosened microtubule doublets slide against each other and through longitudinal overlap, extend for a distance that is up to nine times the original length of the cilium (Warner and Mitchell, 1981). 

Heparin cofactor II, when activated by binding to glycosaminoglycans (dermatan sulfate, heparins, and heparin), inhibits thrombin (24). The 43-kDa serpin, proteinase nexin 1, possesses 30% sequence homology with ATIII and can be activated by binding to heparin to inhibit several serine proteinases including thrombin (25). Proteinase nexin 2 is found within the platelet a-granule and is released when platelets are activated (26). It is able to inhibit factor XIa. 

Other plasminogen activator inhibitors are PAI-3, which is believed to be identical to the activated protein C inhibitor, and proteinase nexin 1, found in the renal epithelial cells, cytosol of fibroblasts, and cardiac myocytes (37, 42, 44, 45). 

Scott R. W., Eaton D. L., Duran N., Baker J. B. Regulation of extracellular plasminogen activator by human fibroblasts. The role of protease nexin. J Biol Chem 1983 258,4397-403. 

Van Nostrand W. E Schmaier A. H., Farrow J. S., Cunningham D. D. Protease nexin-0 (amyloid (3-protein precursor) A platelet a granule protein. Science 1990 248,745-8. 

Baker J. B Low D. A., Simmer R. L. Protease nexin A cellular component that links thrombin and plasminogen activator and mediates their binding to cells. Cell 1980 21, 37-45. 

Another serine protease inhibitor of the al-antitrypsin family (serpin) is heparin cofactor II (HCII), which also forms a 1 1 complex with thrombin, but does not react with factor Xa [4,10]. The rate of inhibition of thrombin is not only increased by heparinoids but also by the related glycosaminoglycan dermatan sulfate. The identification of an inhibitor variant and site-directed mutagenesis studies on HC II cDNA led to the understanding that the binding sites for heparin and dermatan sulfate may be overlapping but not identical. Further proteinase inhibitors interacting with heparinoids are tissue factor pathway inhibitor and protease nexin-1. 

Protease nexin 2 is identical to the secreted form of the amyloid precursor protein containing the Kunitz-type serine protease inhibitor domain (128,129), Protease nexin 2 circulates in blood stored as a platelet a-granule protein, which is secreted upon platelet activation (127). Protease nexin 2 inhibits trypsin- and chymotrypsin-like serine proteases and is also a potent inhibitor of factor Xla (126,127,128). Its location in platelets and its ability to inhibit factor Xla suggests a role in regulating blood coagulation for protease nexin 2. 

Eaton DL, Baker JB. Evidence that a variety of cultured cells secrete protease nexin and produce a distinct cytoplasmic serine protease-binding factor. J Cell Physiol 1983 I 17 175-182. 

PLAT Plasminogen activator, tissue serine (or cysteine) proteinase inhibitor, Clade E (nexin, plasminogen activator inhibitor type 1), member 1... 

A defect or absence in any one of the proteins within the axoneme (e.g. dynein, nexin, etc.) results in cilia that are immotile, so called immotile-cilia syndrome. Patients suffering from this disease have chronic pulmonary disorders due to the cilia in the respiratory tract being unable to sweep out bacteria and other foreign particles. In addition, males with this genetic defect are infertile because their sperm are unable to move due to flagella inactivity. 

Fig. 2. Novel receptor-interacting partners of selected 5-HT receptors, their interaction domains on the receptors, and consequences of the interactions. Abbreviations CaM, Ca2+/calmodulin PDZ, a protein interaction domain termed postsynaptic density 95/discs large/ZO-1 PSD-95, a key protein component of the excitatory postsynaptic density MUPP1, multi-PDZ-domain protein SNX27a, a member of the new sorting nexin family of proteins NHERF, NHE regulatory factor. MUPP1 prevents phosphorylation of serine-458 of the 5-HT2C receptor.

HT4a New sorting nexin (SNX27) Trafficking and targeting of the receptor Carboxyl terminus PDZ domain 340... 

Joubert L, Hanson B, Barthet G, et al. New sorting nexin (SNX27) and NHERF specifically interact with the 5-E n 4u receptor splice variant roles in receptor targeting. J Cell Sci 2004 117 5367-5379. 

In photographs of cilia taken by an electron microscope, several different types of connectors can be seen tying together the individual microtubules (see Figure 3-2). There is a protein that bridges the two central single microtubules in the middle of the cilium. Also, from each of the double microtubules, a radial spoke projects toward the center of the cilium. The structure ends in a knobby mass called the spoke head. Finally, a protein called nexin connects each outer double microtubule to the one beside it. 

Further experiments gave more clues. There are enzymes (called proteases) that have the ability to chew up other proteins, decomposing them into amino acids. When a small amount of a protease is added for a short time to a solution containing cilia, the protease quickly slices up the nexin linkers at the edge of the structure. The rest of the cilium remains intact. The reason that the protease rapidly attacks the linkers is that, unlike the other proteins of the cilium, the nexin linkers are not folded up tightly instead, they are loose, flexible chains. Because they are loose, the protease can cut them as rapidly as a pair of scissors can cut a paper ribbon. (The protease cuts tightly folded proteins as rapidly as scissors cut a closed paperback book.)... 

Proteases allowed biochemists to see how a cilium would work without nexin linkers. What would removal of the linkers do Perhaps the cilium would work just fine without them, or perhaps it would go into rigor mortis as it did when the dynein arms were removed. 

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