کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
5507367 | 1400328 | 2017 | 10 صفحه PDF | دانلود رایگان |
- ALS-causing C71G-PFN1 mutant has been found to severely aggregate in cells.
- C71G-PFN1 causes ALS phenotype and neuron degeneration in mice by a gain of toxicity.
- We show that C71G-PFN1 coexists with the unfold state without any stable structures.
- The unfolded state forms a non-native helical structure in membrane environments.
- C71G-PFN1 might trigger ALS by abnormally interacting with membranes as SOD1 mutants.
Despite having physiological functions completely different from superoxide dismutase 1 (SOD1), profilin 1 (PFN1) also carries mutations causing amyotrophic lateral sclerosis (ALS) with a striking similarity to that triggered by SOD1 mutants. Very recently, the C71G-PFN1 has been demonstrated to cause ALS by a gain of toxicity and the acceleration of motor neuron degeneration preceded the accumulation of its aggregates. Here by atomic-resolution NMR determination of conformations and dynamics of WT-PFN1 and C71G-PFN1 in aqueous buffers and in membrane mimetics DMPC/DHPC bicelle and DPC micelle, we deciphered that: 1) the thermodynamic destabilization by C71G transforms PFN1 into coexistence with the unfolded state, which is lacking of any stable tertiary/secondary structures as well as restricted ps-ns backbone motions, thus fundamentally indistinguishable from ALS-causing SOD1 mutants. 2) Most strikingly, while WT-PFN1 only weakly interacts with DMPC/DHPC bicelle without altering the native structure, C71G-PFN1 acquires abnormal capacity in strongly interacting with DMPC/DHPC bicelle and DPC micelle, energetically driven by transforming the highly disordered unfolded state into a non-native helical structure, similar to what has been previously observed on ALS-causing SOD1 mutants. Our results imply that one potential mechanism for C71G-PFN1 to initiate ALS might be the abnormal interaction with membranes as recently established for SOD1 mutants.
287
Journal: Biochimica et Biophysica Acta (BBA) - Biomembranes - Volume 1859, Issue 11, November 2017, Pages 2161-2170