Structural insights into the role of mutations in amyloidogenesis.

Mechanisms of amyloidogenesis are not well understood, including potential structural contributions of mutations in the process. Our previous research indicated that the dimer interface of amyloidogenic immunoglobulin light chain protein AL-09 is twisted 90 degrees relative to the protein from its germline sequence, kappaI O18/O8. Here we report a systematic restoration of AL-09 to its germline sequence by mutating the non-conservative somatic mutations located in the light chain dimer interface. Among these mutants, we find a correlation between increased thermodynamic stability and an increase in the lag time for fibril formation. The restorative mutant AL-09 H87Y completes the trifecta and restores the dimer interface observed in kappaI O18/O8, emphasizing the potential importance of the structural integrity of these proteins to protect against amyloidogenicity. We also find that adding amyloidogenic mutations into the germline protein illustrates mutational cooperativity in promoting amyloidogenesis.