Immunoglobulin light chain amyloid aggregation

Abstract

Light chain (AL) amyloidosis is a devastating, complex, and incurable protein misfolding disease. It is characterized by an abnormal proliferation of plasma cells (fully differentiated B cells) producing an excess of monoclonal immunoglobulin light chains that are secreted into circulation, where the light chains misfold, aggregate as amyloid fibrils in target organs, and cause organ dysfunction, organ failure, and death. In this article, we will review the factors that contribute to AL amyloidosis complexity, the findings by our laboratory from the last 16 years and the work from other laboratories on understanding the structural, kinetics, and thermodynamic contributions that drive immunoglobulin light chain-associated amyloidosis. We will discuss the role of cofactors and the mechanism of cellular damage. Last, we will review our recent findings on the high resolution structure of AL amyloid fibrils. AL amyloidosis is the best example of protein sequence diversity in misfolding diseases, as each patient has a unique combination of germline donor sequences and multiple amino acid mutations in the protein that forms the amyloid fibril.

Figure 1.

2D topology diagram of immunoglobulin light chain (LC) fold. The nine β-strands that form theframework regions. These strands are connected by unstructured loops in a Greek key pattern. The loops (blue lines) that connect strands B and C, C’, C”, and F and G are determine the specificity of the antigen-antibody interactions, and are known as the complementarity-determining regions (CDRs).

Figure 2.

Light chain amyloidosis pathology. Clonal expansion of plasma cells secreting light chain (LC) dimers that deposit in vital organs as amyloid fibrils.

Figure 3.

Primary structure of an immunoglobulin LC consisting of a variable domain (VL) and a constant domain (CL). A. Crystal structure of an immunoglobulin LC. B. Antibody basic structure, showing the interactions between the LCs and heavy chains (HC) forming a heterotetramer.

Figure 4.

A–C. suggested model of GAG modeof action on AL amyloid fibril formation. The morphological designations/definitions were based on empirical/visual comparison and contrasted with the description of amyloid aggregates and intermediates in the fibril formation pathway, reported for AL proteins as well as other proteins. Adapted from Blancas-Mejia et al., 2015.