In antibody light chain amyloidosis (AL), mutant light chains (LCs) or their variable domains (V_Ls) form fibrils, which accumulate in organs and lead to their failure. The molecular mechanism of this disease is still poorly understood. One of the key open issues is whether the mutant V_Ls and LCs differ in fibril formation. We addressed this question studying the effects of the V_L mutations S20N and R61A within the isolated V_L domain and in the full-length LC scaffold. Both V_L variants readily form fibrils. Here, we find that in the LC context, the S20N variant is protected from fibril formation while for LC R61A fibril formation is even accelerated compared to V_L R61A. Our analyses revealed that the partially unfolded state of the V_L R61A domain destabilizes the C_L domain by non-native interactions, in turn leading to a further unfolding of the V_L domain. In contrast, the folded mutant V_L S20N and V_L wt form native interactions with C_L. These are beneficial for LC stability and promote amyloid resistance. Thus the effects of specific mutations on the V_L fold can have opposing effects on LC domain interactions, stability and amyloidogenicity.

在抗体轻链淀粉样变性（AL）中，突变轻链（LC）或它们的可变域（_VL）形成原纤维，这些原纤维积聚在器官中并导致其衰竭。这种疾病的分子机制仍知之甚少。关键的开放问题之一是突变的_VL和LC在原纤维形成上是否不同。我们解决了这个问题，研究了V _L突变S20N和R61A在分离的V _L结构域和全长LC支架中的作用。两种_VL变体都容易形成原纤维。在这里，我们发现在LC环境中，S20N变体受保护免受原纤维形成，而对于LC R61A，与V _L相比，原纤维形成甚至被加速R61A。我们的分析显示，V _L R61A结构域的部分展开状态通过非天然相互作用破坏了C _L结构域的稳定性，进而导致V _L结构域的进一步展开。相反，折叠的突变体V _L S20N和V _L wt与C _L形成天然相互作用。这些对于LC稳定性和促进淀粉样蛋白抗性是有益的。因此，特定突变对V _L折叠的影响可以对LC结构域的相互作用，稳定性和淀粉样变性产生相反的影响。