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  • Title: The Gelsolin Pathogenic D187N Mutant Exhibits Altered Conformational Stability and Forms Amyloidogenic Oligomers.
    Author: Srivastava A, Singh J, Singh Yadav SP, Arya P, Kalim F, Rose P, Ashish, Kundu B.
    Journal: Biochemistry; 2018 Apr 24; 57(16):2359-2372. PubMed ID: 29637772.
    Abstract:
    Gelsolin is an actin-severing protein that attains an open functional conformation in the presence of Ca2+ or low pH. Mutations (D187N/Y) in the second domain of gelsolin trigger the proteolytic pathway producing amyloidogenic fragments that form the pathological hallmark of gelsolin amyloidosis and lattice corneal dystrophy type 2 (LCD2). Here, we show that the D187N mutant gelsolin in a Ca2+ depleted, low pH-activated, open conformation could assemble into amyloidogenic oligomers without necessarily undergoing the specific proteolytic step. Although both wild-type (WT) and mutant proteins exhibit closely overlapping globular shapes at physiological conditions, the latter exhibits subjugated actin depolymerization, loss of thermodynamic stability, and folding cooperativity. Mutant gelsolin displayed aberrant conformational unwinding and formed structural conformers with high associative properties at low pH conditions. A SAXS intensity profile and Guinier analysis of these conformers showed the formation of unusual, higher order aggregates. Extended incubation at low pH resulted in the formation of thioflavin T and Congo red positive, β-sheet rich aggregates with a fibrillar, amyloid-like morphology visible under electron and atomic force microscopy. Mass spectrometric analysis of disaggregated end-stage fibrils displayed peptide fragments encompassing the entire protein sequence, indicating the involvement of full length mutant gelsolin in fibril formation. Atomistic and REMD simulations indicated a larger increase in solvent accessibility and loss of fold architecture in mutant gelsolin at low pH as compared to WT gelsolin. Our findings support the existence of a secondary oligomerization-dependent aggregation pathway associated with gelsolin amyloidosis and can pave the way for better therapeutic strategies.
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