The Role of Proteolysis in Amyloidosis

Abstract

Amyloidoses are a group of diseases associated with deposits of amyloid fibrils in different tissues. So far, 36 different types of amyloidosis are known, each due to the misfolding and accumulation of a specific protein. Amyloid deposits can be found in several organs, including the heart, brain, kidneys, and spleen, and can affect single or multiple organs. Generally, amyloid-forming proteins become prone to aggregate due to genetic mutations, acquired environmental factors, excessive concentration, or post-translational modifications. Interestingly, amyloid aggregates are often composed of proteolytic fragments, derived from the degradation of precursor proteins by yet unidentified proteases, which display higher amyloidogenic tendency compared to precursor proteins, thus representing an important mechanism in the onset of amyloid-based diseases. In the present review, we summarize the current knowledge on the proteolytic susceptibility of three of the main human amyloidogenic proteins, i.e., transthyretin, β-amyloid precursor protein, and α-synuclein, in the onset of amyloidosis. We also highlight the role that proteolytic enzymes can play in the crosstalk between intestinal inflammation and amyloid-based diseases.

Keywords: amyloid precursor protein; amyloidosis; protein aggregation; proteolysis; synuclein; transthyretin.

Figure 1

Schematic representation of proteolytic cleavage sites (↑) in TTR. The 3D structure (1tta.pdb) (right panel), the secondary structure and amino acid sequence (left panel) of monomeric TTR are shown. β-Strands and α-helices are indicated by blue arrows or red spirals, respectively.

Figure 2

Schematic representation of domain organization and proteolytic cleavage sites (↑) in APP (left panel). The domain architecture and amino acid sequence of the APP are highlighted. E1 and E2 indentify the extracelllar domains, KPI is the Kunitz-type domain, while TM is the trans-membrane domain and AICD is the APP intracellular domain. Schematic representation of the APP threedimensional structure (right panel). The protein cartoon is obtained by combining different crystal structures (1zjd.pbd; 2llm.pdb; 3dx0.pdb; 3kzm.pdb; 3umk.pdb) of APP domains. The arrows approximately indicate where the cleavage sites are found on the APP structure.

Figure 3

(Top panel) Schematic representation of membrane-bound structure (1xq8.pdb) of αSyn; NT is the N-terminal domain 1-60, NAC refers to the Non-Amyloid Component 61-95, and CT corresponds to the C-terminal region 96-140. (Bottom panel) Domain architecture, amino acid sequence and proteolytic cleavage sites (↑) of αSyn by different proteases, i.e., calpain-1 (C), cathepsin (Cat) B, D and L, matrix metallo-proteinase-3 (MMP3), neurosin (N), and plasmin (P).

Figure 4

Amyloid aggregation profiles of TTR, APP and αSyn. The predicted aggregation propensities were obtained using the MetAmyl tool [121]. Regions of low structural stability correspond to the highest peaks in the aggregation propensity profiles (hexapeptide amyloidogenicity). The grey bars represent the regions susceptible to proteolytic attack, to generate amyloidogenic species.