Dataset Information

Structural Modulation of Human Amylin Protofilaments by Naturally Occurring Mutations.

ABSTRACT: Human islet amyloid polypeptide (hIAPP), also known as amylin, is a 37-amino-acid peptide, co-secreted with insulin, and widely found in fibril form in type-2 diabetes patients. By using all-atom molecular dynamics simulations, we study hIAPP fibril segments (i.e., fibrillar oligomers) formed with sequences of naturally occurring variants from cat, rat, and pig, presenting different aggregation propensities. We characterize the effect of mutations on the structural dynamics of solution-formed hIAPP fibril models built from solid-state NMR data. Results from this study are in agreement with experimental observations regarding their respective relative aggregation propensities. We analyze in detail the specific structural characteristics and infer mechanisms that modulate the conformational stability of amylin fibrils. Results provide a platform for further studies and the design of new drugs that could interfere with amylin aggregation and its cytotoxicity. One particular mutation, N31K, has fibril-destabilizing properties, and could potentially improve the solubility of therapeutic amylin analogs.

SUBMITTER: Tofoleanu F

PROVIDER: S-EPMC6428083 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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Structural Modulation of Human Amylin Protofilaments by Naturally Occurring Mutations.

Tofoleanu Florentina F Yuan Ye Y Pickard Frank C FC Tywoniuk Bartłomiej B Brooks Bernard R BR Buchete Nicolae-Viorel NV

The journal of physical chemistry. B 20180221 21

Human islet amyloid polypeptide (hIAPP), also known as amylin, is a 37-amino-acid peptide, co-secreted with insulin, and widely found in fibril form in type-2 diabetes patients. By using all-atom molecular dynamics simulations, we study hIAPP fibril segments (i.e., fibrillar oligomers) formed with sequences of naturally occurring variants from cat, rat, and pig, presenting different aggregation propensities. We characterize the effect of mutations on the structural dynamics of solution-formed hI ...[more]

PMID: 29406755

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Project description:Sequencing of Ebola virus (EBOV) genomes during the 2014-2016 epidemic identified several naturally occurring, dominant mutations potentially impacting virulence or tropism. In this study, we characterized EBOV variants carrying one of the following substitutions: A82V in the glycoprotein (GP), R111C in the nucleoprotein (NP), or D759G in the RNA-dependent RNA polymerase (L). Compared with the wild-type (WT) EBOV C07 isolate, NP and L mutants conferred a replication advantage in monkey Vero E6, human A549, and insectivorous bat Tb1.Lu cells, while L mutants displayed a disadvantage in human Huh7 cells. The replication of the GP mutant was significantly delayed in Tb1.Lu cells and similar to that of the WT in other cells. The L mutant was less virulent, as evidenced by increased survival for mice and a significantly delayed time to death for ferrets, but increased lengths of the period of EBOV shedding may have contributed to the prolonged epidemic. Our results show that single substitutions can have observable impacts on EBOV pathogenicity and provide a framework for the study of other mutations.IMPORTANCE During the Ebola virus (EBOV) disease outbreak in West Africa in 2014-2016, it was discovered that several mutations in the virus emerged and became prevalent in the human population. This suggests that these mutations may play a role impacting viral fitness. We investigated three of these previously identified mutations (in the glycoprotein [GP], nucleoprotein [NP], or RNA-dependent RNA polymerase [L]) in cell culture, as well as in mice and ferrets, by generating recombinant viruses (based on an early West African EBOV strain) each carrying one of these mutations. The NP and L mutations appear to decrease virulence, whereas the GP mutation slightly increases virulence but mainly impacts viral tropism. Our results show that these single mutations can impact EBOV virulence in animals and have implications for the rational design of efficacious antiviral therapies against these infections.

Dataset Information

Structural Modulation of Human Amylin Protofilaments by Naturally Occurring Mutations.

Publications

Structural Modulation of Human Amylin Protofilaments by Naturally Occurring Mutations.

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