The N-terminal strand modulates immunoglobulin light chain fibrillogenesis

详细信息    查看全文

• 作者：Luis del Pozo-Yauner ; Jonathan S. Wall ; Mart铆n Gonz谩lez Andrade ; Rosana S谩nchez-L贸pez ; S ; ra L. Rodr铆guez-Ambriz ; Julio I. P茅rez Carre贸n ; Adri谩n Ochoa-Leyva ; D. Alej ; ro Fern谩ndez-Velasco
• 关键词：Light chain ; Amyloid ; Misfolding ; Aggregation ; Folding thermodynamics
• 刊名：Biochemical and Biophysical Research Communications
• 出版年：10 January, 2014
• 年：2014
• 卷：443
• 期：2
• 页码：495-499
• 全文大小：887 K

文摘

It has been suggested that the N-terminal strand of the light chain variable domain (V_L) protects the molecule from aggregation by hindering spurious intermolecular contacts. We evaluated the impact of mutations in the N-terminal strand on the thermodynamic stability and kinetic of fibrillogenesis of the V_L protein 6aJL2. Mutations in this strand destabilized the protein in a position-dependent manner, accelerating the fibrillogenesis by shortening the lag time; an effect that correlated with the extent of destabilization. In contrast, the effect on the kinetics of fibril elongation, as assessed in seeding experiments was of different nature, as it was not directly dependant on the degree of destabilization. This finding suggests different factors drive the nucleation-dependent and elongation phases of light chain fibrillogenesis. Finally, taking advantage of the dependence of the Trp fluorescence upon environment, four single Trp substitutions were made in the N-terminal strand, and changes in solvent exposure during aggregation were evaluated by acrylamide-quenching. The results suggest that the N-terminal strand is buried in the fibrillar state of 6aJL2 protein. This finding suggest a possible explanation for the modulating effect exerted by the mutations in this strand on the aggregation behavior of 6aJL2 protein.