Systemic amyloidoses

Abstract

The amyloidoses are a group of protein misfolding diseases in which the precursor protein undergoes a conformational change that triggers the formation of amyloid fibrils in different tissues and organs, causing cell death and organ failure. Amyloidoses can be either localized or systemic. In localized amyloidosis, amyloid deposits form at the site of precursor protein synthesis, whereas in systemic amyloidosis, amyloid deposition occurs distant from the site of precursor protein secretion. We review the type of proteins and cells involved and what is known about the complex pathophysiology of these diseases. We focus on light chain amyloidosis to illustrate how biochemical and biophysical studies have led to a deeper understanding of the pathogenesis of this devastating disease. We also review current cellular, tissue, and animal models and discuss the challenges and opportunities for future studies of the systemic amyloidoses.

Figure 1

Amyloid fibril structure showing conversion from natively folded protein to partially unfolded intermediate to amyloid fibril. Electron microscopy images show different morphologies of amyloid fibrils.

Figure 2

Light chain (AL) amyloidosis pathology A) clonal expansion of plasma cells secreting light chain dimers that deposit in vital organs as amyloid fibrils B) Immunoglobulin structure showing two identical heavy chains (HC) and two identical light chains (LC) linked together via covalent interchain disulfide bonds.

Figure 3

(a) X-ray structure of κIgG antibody (PDB code: 1IGT). Two heavy chains (green), and two light chains (gold) assemble in a heterotetramer. (b) Structure of full length light chain (PDB code: 1IGT, chain A). Both the C_L (red) and V_L (yellow) domains present a characteristic immunoglobulin fold. (c) Structural alignment of X-ray crystal structures of λV_L 6aJL2 germline (gold) and κV_L κ1 O18/O8JK2 (red) germline proteins (PDB code: 2W0K and 2Q20, respectively). The FR region shows a very similar structure while the CDRs (blue) show significant differences as a result of high variability in the sequence. κ and λ germline proteins present a highly conserved single tryptophan residue at position 35 (black sticks), in close proximity of the characteristic immunoglobulin disulfide bridge (gray sticks).

Figure 4

This morph animation show the transition between three unique dimer orientation present in the crystal structures of κI O18/O8 and AL-09, as well as NMR structure of κI Y87H in order to see and understand the structural differences between them. This animation does not represent genuine conformational changes. Surface representation of the residues in the monomer A involved in the κI dimer interface is colored in magenta while residues outside the dimer interface are shown in cyan. Monomer B (ribbons) of AL-09 (blue, PDB code: 2Q1E), κV_L κI O18/O8 (gold, PDB code: 2Q20), κI Y87H (red, PDB code: 2KQM) show a ~90° and ~ 180° rotation to the monomer A from the canonical dimer interface respectively. In yellow ribbon is shown the differences in dimer structures as the hands on a clock moving in intervals of 90°. Interface residues Q3, Y36, F98 and Q100 (red sticks) show the biggest conformational differences between dimer interfaces.

Figure 5

Structural comparison between the N-Terminal region of (a) λV_L proteins and (b) κV_L proteins (PDB codes: 2W0K, 2W0L, 3B5G, 1CD0, 1PW3, 1PEW, 2CD0, 2Q20, 2KQN, 3CDY, 2Q1E, 3DVI, 2KQM, 3CDC, 3DVF respectively). Significant differences in the N-terminal region are observed. κV_L proteins present more H-bond (cyan lines) interactions between β-strand A (gold) and the edges of β-strands B (green) and β-strand G (red). In both proteins β-strand A adopts a characteristic conformation known as “β-sheet switch”, which has been proposed to protect the two edge β-strands B and G from non-native intermolecular interactions that lead to aggregation. The topology of the N-terminal region in both germline sequences is similar and includes a β-bulge (residues 7-8) between two segments of β-strand A. Interestingly, the size of the β-bulge in κV_L is greater than in λV_L proteins, and κV_L presents more contacts between β-strand A and the C-terminus and β-strand B than λV_L. Red circles indicate the β-bulge motif in β-strand G. CDRs are at the bottom of the models.