The effect of membranes on the in vitro fibrillation of an amyloidogenic light-chain variable-domain SMA.
Light chain (or AL) amyloidosis is the most common form of systemic amyloidosis, characterized by the pathological deposition of insoluble fibrils of immunoglobulin light-chain fragments in various organs and tissues, especially in the kidney and heart. Both the triggering factors and the mechanisms involved in the abnormal formation of the insoluble fibrillar aggregates from the soluble proteins are poorly understood. For example, although the fibrillar deposits are typically found associated with the extracellular matrix and basement membranes, it is not clear whether fibrils are initially formed intra- or extracellularly, nor it is understood what determines where the deposits will occur; i.e., site tropism. In the present investigation, we studied the interaction of a recombinant amyloidogenic light-chain variable domain, SMA, with lipid vesicles. The nature of the interaction was dependent on the lipid composition and the SMA to lipid ratio. The most pronounced effect was found from vesicles composed of 1,2-dipalmitoyl-sn-glycero-3-phosphocholine/1-palmitoyl-2-oleoyl-sn-glycero-3-phosphate, which dramatically accelerated fibril growth. Interestingly, spectral probes, such as intrinsic fluorescence and far-UV CD spectroscopy did not show significant conformational changes in the presence of the vesicles. The presence of cholesterol or divalent cations, such as Ca(2+) and Mg(2+), lead to decreased membrane-induced SMA fibrillation. Thus, membranes may have significant effects on light-chain fibrillation and may contribute to the site selectivity observed in AL amyloidosis.
Meng
Xiaoyun
X
Department of Chemistry, University of California at Santa Cruz, Santa Cruz, CA 95064, USA.
Fink
Anthony L
AL
Uversky
Vladimir N
VN
D000682:Amyloid / Q000737:chemistry* / Q000378:metabolism* / Q000648:ultrastructure; D002118:Calcium / Q000494:pharmacology; D002784:Cholesterol / Q000494:pharmacology; D005453:Fluorescence; D006863:Hydrogen-Ion Concentration / Q000187:drug effects; D007147:Immunoglobulin Light Chains / Q000378:metabolism* / Q000648:ultrastructure; D007700:Kinetics; D010743:Phospholipids / Q000378:metabolism; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D017550:Spectroscopy, Fourier Transform Infrared; D053835:Unilamellar Liposomes / Q000494:pharmacology*
D000682:Amyloid; D007147:Immunoglobulin Light Chains; D010743:Phospholipids; D053835:Unilamellar Liposomes; D002784:Cholesterol; D002118:Calcium