Apolipoprotein A-I Associated Amyloidoses: The Intriguing Case of a Natively Unfolded Protein Fragment

Abstract

Nowadays, a main challenge for scientists is that of drawing a comprehensive picture, in which common traits shared by the amyloidogenic proteins identified so far, structurally and functionally different from one another, are depicted. From a structural point of view, a clear relationship between protein sequences and aggregation does not exist, although proteins able to aggregate in general are characterized by a low sequence complexity (Wootton & Federhen, 1996) and/or high net charge coupled with low mean hydrophobicity (Gast et al., 1995), as well as by the abundance of residues favouring the -sheet secondary structure (Steward et al., 2002). From a functional point of view, amyloidogenic proteins are associated to a variety of cellular functions and activities, and in some cases their biological function is unknown. As for the localization of the disease, amyloidoses may be localized in the nervous system, as those implicated in neurodegenerative diseases, or may be systemic when target tissues for amyloid deposition are in peripheral organs. Two main classes of fibrillogenic proteins have been identified: those with a compact folding in their native state and those that are partially unfolded. Studies on pre-amyloid order-disorder transitions are central to understand both the assembly mechanisms and the disease molecular bases. In the case of amyloidogenic proteins that are natively folded, destabilizing mutations and/or changes in solution conditions are key factors responsible for the induction of fibrillogenesis, as in the case of 2-microglobulin (A2M) or the prion protein APrP (Chiti & Dobson, 2006). On the other hand, several amyloidogenic proteins or polypeptides are intrinsically disordered. Such proteins include the β-Amyloid peptide (A), islet amyloid polypeptide (AIAPP) and ┙-synuclein (Abedini & Raleigh, 2009). These “natively unfolded” (Weinreb et al., 1996) proteins emerged as proteins lacking of almost any secondary structure and were shown to be extremely flexible and disordered under physiological conditions (Uversky, 2002). The main feature of these proteins is the intrinsic structural plasticity, as a disorder to order transition may occur upon functioning (Abedini & Raleigh, 2009). In some cases, natively folded proteins generate unfolded fragments associated to the amyloid pathology. This may occur when a specific mutation diverts the fate of a globular