Microtubule-associated proteins structural

Several pathological self-polymerizing systems have been biophysi-cally characterized sufficiently to permit identification of protein or peptide species that could serve as molecular targets in a structure-activity relationship. These include transthyretin (TTR) [73-76], serum amyloid A protein (SAA) [77], microtubule-associated protein tau [78-80], amylin or islet amyloid polypeptide (IAPP) [81,82], IgG light chain amyloidosis (AL) [83-85], polyglutamine diseases [9,86], a-synuclein [47,48] and the Alzheimer s (3 peptide [87-96]. A variety of A(3 peptide assay systems have been established at Parke-Davis to search for inhibitors of fibril formation that could be therapeutically useful [97]. 

With regard to microtubular ultrastructure, micro filaments (5-7 run in diameter) are composed of filamentous actin. The tubule-like structures are formed by a, P-tubulin heterodimers. The wall is composed of 13 parallel protofilaments. Various microtubule-associated proteins and motor proteins (kinesin and dynein) are bound to the wall. The microtubule is a polar structure, i.e., plus and minus ends. 

In resting neutrophils it is estimated that there are about 11-23 microtubules per cell, with a diameter of approximately 25 nm and a wall width of 5 nm. They are long, tubular structures made by the helical formation of tubulin molecules, which are either a- or /3-subunits, each with a relative molecular mass of 55 kDa (Fig. 4.9). Each subunit is present in equimolar amounts in a tubulin molecule, and these subunits exist as dimers of one a- and one /3-subunit. Because microtubules are polar, growth of the fibre is biased towards one end, termed the plus end. A number of microtubule-associated proteins (MAPs) affect the dynamic shape of the microtubule, and in the resting neutrophil about 35-40% of the tubulin pool is assembled, whilst the remainder can be assembled very rapidly after cell stimulation. 

The basic biology and pharmacology of Epo B (as the most potent and most widely studied natural epothilone) have been summarized in several previous review articles.As indicated in Section 1.1, the biological effects of the compound are based on its ability to bind to microtubules and alter the intrinsic stabihty and dynamic properties of these supramolecular structures. In cell-free in vitro systems, this is demonstrated by the prevention of Ca - or cold-induced depolymerization of preformed microtubule polymers as well as by the promotion of tubuhn polymerization (to form microtubule-like polymers) in the absence of either microtubule-associated proteins (MAPs) and/or guanosine triphosphate (GTP), at temperatures significantly below 37 °C, and in the presence of The latter... 

Ledesma MD, Bonay P, Colaco C, Avila J (1994) Analysis of microtubule-associated protein tau glycation in paired helical filaments. J Biol Chem 269 21614-21619 Lee G (1990) Tau protein an update on structure and function. Cell Motil Cytoskeleton 15 199-203... 

AvUa J. Microtubule Proteins. 1989. CRC Press, Boca Raton, FL. This book covers various aspects of microtubule and microtubule-associated proteins. In addition, detailed descriptions of the relationship between microtubule structure and functions, microtubule proteins, it elaborates microtubule dynamics, and microtubule poisons. 

Neurofibrillary tangles are found within neurons of the cerebral cortex and hippocampus and consist of insoluble intracellular fibrils that are comprised of hyperphosphorylated forms of tau, a microtubule-associated protein [20,21], The microtubules are essential for axonal transport and the structural stability of neuronal processes. Therefore, it is believed that impaired axonal transport contributes to neuronal degeneration that typifies the disease. Neurofibrillary tangles are not imique to Alzheimer s disease and can be foimd in a variety of other neurologic disorders. 

Among the structural proteins which are subject to GSK-3 regulation, the microtubule-associated protein tau is a prime target in Alzheimer s disease pathology. Tau binds to tubulin and promotes microtubule assembly and stability in a phosphorylation-dependent manner. The phosphorylation status of tau is balanced by antagonistic kinase and phosphate activities. Inappropriate hyperphosphorylation of tau is a key event in contributing to cytoskeletal abnormalities and tau pathology in Alzheimer s disease. When hyperphos-phorylated, tau s affinity for the microtubule is reduced and as a consequence tau dissociates from the microtubules. This leads to abnormal accumulation... 

A large number of proteins influence the assembly and stability of microtubules and their association with other cell structures (Table 20-1). These proteins are collectively called microtubule-associated proteins (MAPs) because most co purify with microtubules isolated from cells. The results of Immunofluorescence localization studies also have shown a parallel distribution of MAPs and microtubules in cells— strong evidence for their interaction In vivo. 

In an interphase fibroblast cell, cytosolic microtubules are arranged in a distinctive hub-and-spoke array that lies at the center of a cell (Figure 2 0-13a). The microtubule spokes radiate from a central site occupied by the centrosome, which is the primary microtubule-organizing center in many interphase cells. We will use the term MTOC to refer to any of the structures used by cells to nucleate and organize microtubules. In animal cells, the MTOC is usually a centrosome, a collection of microtubule-associated proteins that sometimes but not always contains a pair of centrioles (Figure... 

---