Biological activity and pathological implications of misfolded proteins |
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Authors: | V Bellotti P Mangione M Stoppini |
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Institution: | (1) Dipartimento di Biochimica, Università degli Studi di Pavia, via Taramelli 3b, I-27100 Pavia (Italy), Fax +39 382 423108, e-mail: vbellot@unipv.it, IT;(2) Research Laboratory of Biotechnology, IRCCS Policlinico S. Matteo, P.le Golgi 2, I-27100 Pavia (Italy), IT |
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Abstract: | The physiological metabolism of proteins guarantees that different cellular compartments contain the appropriate concentration
of proteins to perform their biological functions and, after a variable period of wear and tear, mediates their natural catabolism.
The equilibrium between protein synthesis and catabolism ensures an effective turnover, but hereditary or acquired abnormalities
of protein structure can provoke a premature loss of biological function, an accelerated catabolism and diseases caused by
the loss of an irreplaceable function. In certain proteins, abnormal structure and metabolism are associated with a strong
tendency to self-aggregation into a polymeric fibrillar structure, and in these cases the disease is not principally caused
by the loss of an irreplaceable function but by the action of this new biological entity. Amyloid fibrils are an apparently
inert, insoluble, mainly extracellular protein polymer that kills the cell without tissue necrosis but by activation of the
apoptotic mechanism. We analyzed the data reported so far on the structural and functional properties of four prototypic proteins
with well-known biological functions (lysozyme, transthyretin, β2-microglobulin and apolipoprotein AI) that are able to create
amyloid fibrils under certain conditions, with the perspective of evaluating whether the achievement of biological function
favors or inhibits the process of fibril formation. Furthermore, studying the biological functions carried out by amyloid
fibrils reveals new types of protein-protein interactions in the transmission of messages to cells and may provide new ideas
for effective therapeutic strategies.
Received 9 November 1998; received after revision 15 January 1999; accepted 15 January 1999 |
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Keywords: | , Amyloidosis, protein misfolding, lysozyme, β,2-microglobulin, apolipoprotein AI, transthyretin, β, protein, |
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