Protein misfolding, aggregation and other factors determining the amyloidogenic landscape of human leucocyte chemotaxin-2: A review

Abstract

Amyloidosis refers to a group of diseases characterized by the deposition of insoluble protein fibrils in various tissues and organ systems. Several proteins are reported to form amyloid under varying conditions, some of them are well characterized, e.g. Alzheimer's and Parkinson's. Though amyloid depositions affect all body parts, the organs most affected by amyloid deposition are the brain, kidneys, and liver. This manuscript focuses on human leucocyte chemotaxin-2, a recently identified protein involved in amyloid formation. Leukocyte cell-derived chemotaxis-2 (LECT2), a secretory protein that mainly acts as a chemotactic factor. It regulates TNF signaling in macrophages and osteo lineage cells, influencing hematopoietic stems cells (HSC) expansion and mobilization. LECT2 misfolding and aggregation mostly causes the deposition of amyloids, primarily in the kidney and spleen. Amyloid form of LECT2 (ALECT2) has a strong racial bias being highly prevalent in the Hispanic population. The precise mechanism of LECT2's action in amyloidosis is mainly unknown and thus hinders the development of therapeutic intervention, kidney transplant remains therefore the most effective treatment for ALECT2. This review shall foster insights about structure, function and the key factors responsible for the LECT2 amyloidosis. LECT2 transcript encodes four different splice variants in humans and one among these four transcripts shows' expression specifically in liver, testes and prostate. LECT2 protein sequence is highly conserved in higher vertebrates indicating its functional importance across species and genera. Specifically, the amyloid forming region is highly conserved except its slight variation in birds indicating difference in amyloid forming capabilities in this group. A single SNP variation causing substitution of isoleucine in place of valine is particularly documented to be important for amyloid formation.

Keywords: Amyloid; Leucocyte chemotoxin 2; Protein misfolding; Renal amyloidosis.