کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
5371017 | 1503926 | 2014 | 8 صفحه PDF | دانلود رایگان |
- The acidic environment results in the loose structure of TTR dimer.
- Mutation L55P causes the disruption of strand D and makes CE-loop very flexible.
- Strand D plays an important role in protecting strand C.
- The movements of strand C is the beginning of the unfolding process.
- TTR dimer would dissociate into monomer before fibrillation.
Transthyretin (TTR) dissociation and aggregation appear to cause several amyloid diseases. TTR dimer is an important intermediate that is hard to be observed from the biological experiments. To date, the molecular origin and the structural motifs for TTR dimer dissociation, as well as the unfolding process have not been rationalized at atomic resolution. To this end, we have investigated the effect of low pH and mutation L55P on stability as well as the unfolding pathway of TTR dimer using constant pH molecular dynamics simulations. The result shows that acidic environment results in loose TTR dimer structure. Mutation L55P causes the disruption of strand D and makes the CE-loop very flexible. In acidic conditions, dimeric L55P mutant exhibits notable conformation changes and an evident trend to separate. Our work shows that the movements of strand C and the loops nearby are the beginning of the unfolding process. In addition, hydrogen bond network at the interface of the two monomers plays a part in stabilizing TTR dimer. The dynamic investigation on TTR dimer provides important insights into the structure-function relationships of TTR, and rationalizes the structural origin for the tendency of unfolding and changes of structure that occur upon introduction of mutation and pH along the TTR dimer dissociation and unfolding process.
Journal: Biophysical Chemistry - Volume 189, May 2014, Pages 8-15