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Structural alterations within native amyloidogenic immunoglobulin light chains.

ABSTRACT: Amyloid diseases are characterized by the misfolding of a precursor protein that leads to amyloid fibril formation. Despite the fact that there are different precursors, some commonalities in the misfolding mechanism are thought to exist. In light chain amyloidosis (AL), the immunoglobulin light chain forms amyloid fibrils that deposit in the extracellular space of vital organs. AL proteins are thermodynamically destabilized compared to non-amyloidogenic proteins and some studies have linked this instability to increased fibril formation rates. Here we present the crystal structures of two highly homologous AL proteins, AL-12 and AL-103. This structural study shows that these proteins retain the canonical germ line dimer interface. We highlight important structural alterations in two loops flanking the dimer interface and correlate these results with the somatic mutations present in AL-12 and AL-103. We suggest that these alterations are informative structural features that are likely contributing to protein instability that leads to conformational changes involved in the initial events of amyloid formation.

SUBMITTER: Randles EG

PROVIDER: S-EPMC2840394 | biostudies-literature | 2009 May

REPOSITORIES: biostudies-literature

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Structural alterations within native amyloidogenic immunoglobulin light chains.

Randles Edward G EG Thompson James R JR Martin Douglas J DJ Ramirez-Alvarado Marina M

Journal of molecular biology 20090408 1

Amyloid diseases are characterized by the misfolding of a precursor protein that leads to amyloid fibril formation. Despite the fact that there are different precursors, some commonalities in the misfolding mechanism are thought to exist. In light chain amyloidosis (AL), the immunoglobulin light chain forms amyloid fibrils that deposit in the extracellular space of vital organs. AL proteins are thermodynamically destabilized compared to non-amyloidogenic proteins and some studies have linked thi ...[more]

PMID: 19361523

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Project description:The present study aimed to investigate the toxic effects of different amyloidogenic light-chains (LCs) on cardiomyocytes, and demonstrate the differentially expressed genes (DEGs) and signaling pathways that participate in this process. Cultured cardiomyocytes were treated with recombinant ? LC peptide (AL-09) or with serum from a patient diagnosed with multiple myeloma (? LC) with cardiac involvement. The 6xHis peptide or serum from healthy patients was used as peptide control or serum control, respectively. Cell viability was determined using CCK-8 assay and apoptosis was analyzed by flow cytometry. The DEGs were detected by RNA sequencing (RNA-Seq), followed by Gene Ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. Changes in gene expression levels were confirmed by reverse transcription-quantitative PCR. The cell viability in the AL-09 peptide-treated (0.2 mg/ml) and patient serum-treated (1:10 dilution) cardiomyocytes decreased to 42 and -72% of the corresponding control groups. The extent of cell apoptosis increased in AL-09-treated cardiomyocytes compared with the control group. RNA-Seq showed 256 DEGs co-existed in the two paired groups, including 127 upregulated and 88 downregulated genes. The KEGG pathways for upregulated expressed genes included the 'TGF-? signaling pathway', the 'Hedgehog signaling pathway', the 'ErbB signaling pathway' and 'lysine degradation'. The higher mRNA expression of bone morphogenetic protein (Bmp) 4, Bmp6, prostaglandin G/H synthase (Ptgs)1, Ptgs2, epiregulin, Tgfa and procollagen-lysine,2-oxoglutarate 5-dioxygenase 2 were confirmed. The KEGG pathways of downregulated expressed genes included genes involved with the 'p53 signaling pathway' and the 'cell cycle'. The mRNA expression levels of E3 ubiquitin-protein ligase CCNB1IP1 showed significant downregulation in the AL-09 peptide group compared with those in the 6xHis peptide group. In conclusion, cardiomyocytes treated with amyloidogenic ? and ? LCs presented with decreased cell viability compared with controls. Cell apoptosis increased in ? LC-treated cells compared with controls. The gene expression profiles associated with transforming growth factor-?-bone morphogenetic protein, the receptor tyrosine-protein kinase erbB-2 signaling pathways, prostaglandins, collagen production, the p53 signaling pathway and the cell cycle were altered in light-chain-treated cardiomyocytes.

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Structural alterations within native amyloidogenic immunoglobulin light chains.

Publications

Structural alterations within native amyloidogenic immunoglobulin light chains.

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