Immunoglobulin kappa light chain and its amyloidogenic mutants: a molecular dynamics study.
AL amyloidosis and LCDD are pathological conditions caused by extracellural deposition of monoclonal Ig light chain variable domains. In the former case, deposits have a form of amyloid fibrils, in the latter, amorphous aggregates. 1REI kappa light chain variable domain and its two point mutants, R61N and D82I, were chosen for the analysis in this work. Wild 1REI does not create deposits in vitro, while R61N aggregates as amyloid fibrils and D82I creates amorphous aggregates. Both mutated residues create a conserved salt bridge; thus, substitution of any of them should decrease V(L) domain stability. For these three proteins, 5 ns MD simulations were conducted in temperatures of 300 K and 400 K, with protonated and unprotonated acidic residues, mimicking acidic and neutral experimental pH conditions (3 sets: N300, N400, and A400). The analysis of trajectories focused on characterization of changes in conformational behavior and stability of Ig kappa light chain variable domain caused by single aminoacid substitutions that were experimentally proved to enhance aggregation propensity, both in the form of amyloid and amorphous aggregates. Residue D82 turns out to be involved not only in R61-D82 but also in K45-D82 interaction, which was not observed in the X-ray structure, but frequently populated simulations of 1REI. The substitution D82I excludes both interactions, resulting in substantial destabilization (i.e., easier aggregation). Examination of behavior of edge regions of V(L) beta-sandwich reveals significant alterations in D82I mutant compared to wild 1REI, while relatively small changes occur in R61N. This suggests that mild and slow destabilization is the reason of the conversion of V(L) to partially folded amyloidogenic intermediate structure.
Nowak
Mateusz
M
Department of Biostatistics and Medical Informatics, Collegium Medicum, and Faculty of Biotechnology, Jagiellonian University, Kraków, Poland. mynowak@cyf-kr.edu.pl
D024342:Amino Acids, Acidic / Q000737:chemistry; D000686:Amyloidosis / Q000235:genetics*; D003198:Computer Simulation; D006860:Hydrogen Bonding; D007145:Immunoglobulin kappa-Chains / Q000737:chemistry* / Q000235:genetics*; D008958:Models, Molecular; D017354:Point Mutation; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D011522:Protons
D024342:Amino Acids, Acidic; D007145:Immunoglobulin kappa-Chains; D011522:Protons