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Parkinson's
TPPP/p25
MT/membrane
„bundling”
Fig. 7.2 Connection between glycolysis and neurodegenerative disorders: interaction of glyco-
lytic enzymes attached to microtubule/membrane with pathological proteins resulting in mutual
functional effects (Modified Fig. 5 from Ovadi et al.
2004
)
precursor protein affects the functions of the dehydrogenase (Mazzola and Sirover
2003
) (cf. Fig.
7.2
). Cytoskeletal filaments are also targets of GAPDH and involve
microfilaments or microtubules depending on the cell type (Ovadi and Srere
2000
).
GAPDH also associates with nucleic acids in the nucleus as well as in the cyto-
plasm. In summary, the different functions of GAPDH can be switched on by
multiple factors so as to activate apparently unrelated pathways (Jeffery
1999
).
Unlike classical cases in which moonlighting proteins display distinct physio-
logical functions, there are situations that involve their functions being perverted, a
pathological switch that may put these proteins into a specific subset of moonlight-
ing proteins termed
neomoonlighting
proteins (Jeffery
2011
). This pathological
switch is based on different mechanisms and is characteristic of structurally
unfolded (disordered) proteins with extensive capacity to adopt different
conformations upon binding distinct partners.
Many of the neomoonlighting proteins do not have stable, well-defined 3D
structures; consequently, they are liable to form pathological ultrastructures, such
as fibrils, oligomers, or aggregates with distinct toxicity. Although the molecular
events that initiate formation of these ultrastructures, such as aberrant
protein-protein interactions, are similar in many “disordered diseases,” the out-
come as the clinical symptoms can be very different (Ovadi and Orosz
2009
). The
conformational instability of the neomoonlighting proteins can contribute exten-
sively to the complex phenotype of a given disorder. Thus, a full characterization of
the proteome is essential for understanding the pathological mechanisms of human
diseases.
An established example is the Tubulin Polymerization Promoting Protein,
TPPP/p25, a disordered protein that is abundant in the pathological human brain
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