Dataset Information

Aggregation of Chameleon Peptides: Implications of ?-Helicity in Fibril Formation.

ABSTRACT: We investigate the relationship between the inherent secondary structure and aggregation propensity of peptides containing chameleon sequences (i.e., sequences that can adopt either ? or ? structure depending on context) using a combination of replica exchange molecular dynamics simulations, ion-mobility mass spectrometry, circular dichroism, and transmission electron microscopy. We focus on an eight-residue long chameleon sequence that can adopt an ?-helical structure in the context of the iron-binding protein from Bacillus anthracis (PDB id 1JIG ) and a ?-strand in the context of the baculovirus P35 protein (PDB id 1P35 ). We show that the isolated chameleon sequence is intrinsically disordered, interconverting between ?-helical and ?-rich conformations. The inherent conformational plasticity of the sequence can be constrained by addition of flanking residues with a given secondary structure propensity. Intriguingly, we show that the chameleon sequence with helical flanking residues aggregates rapidly into fibrils, whereas the chameleon sequence with flanking residues that favor ?-conformations has weak aggregation propensity. This work sheds new insights into the possible role of ?-helical intermediates in fibril formation.

SUBMITTER: Kim B

PROVIDER: S-EPMC4936924 | biostudies-literature | 2016 Jul

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Aggregation of Chameleon Peptides: Implications of α-Helicity in Fibril Formation.

Kim Bongkeun B Do Thanh D TD Hayden Eric Y EY Teplow David B DB Bowers Michael T MT Shea Joan-Emma JE

The journal of physical chemistry. B 20160401 26

We investigate the relationship between the inherent secondary structure and aggregation propensity of peptides containing chameleon sequences (i.e., sequences that can adopt either α or β structure depending on context) using a combination of replica exchange molecular dynamics simulations, ion-mobility mass spectrometry, circular dichroism, and transmission electron microscopy. We focus on an eight-residue long chameleon sequence that can adopt an α-helical structure in the context of the iron ...[more]

PMID: 27001160

Similar Datasets

Project description:Amorphous aggregation is a major problem for protein biopharmaceuticals, and aggregate formation in a drug formulation can have serious health implications for the patient. In many cases, an immunogenic response is generated from the administration of a drug product containing aggregated protein. This becomes especially significant when the patient requires long-term or repeated administration of the drug, because the likelihood of a severe immune response increases. While the prevention of protein aggregation is critically important for the future of protein pharmaceuticals, the mechanism of amorphous aggregation is still poorly understood. The lack of understanding regarding nonfibrillar aggregation is largely due to the fact that assembly is difficult to study. In particular the role that various structural features (i.e., alpha-helix, beta-structure, disulfide bonds) play in the aggregation process varies with the amino acid sequence and is dependent upon tertiary structure and solution conditions. Well-structured proteins do not readily aggregate in solution, whereas partially unfolded proteins tend to aggregate rapidly and often become insoluble. Here, we present a unique and simple system for studying amorphous protein aggregation. We have previously reported the isolation of the basic leucine zipper (bZIP) domain of activating transcription factor 5 (ATF5), a protein notable for its potential as a pharmaceutical target for treatment of glioblastoma multiforme. This domain consists of a single alpha-helix and possesses a single cysteine residue. It is only partially structured and displays marginal stability in solution under physiological conditions. We have modulated solution conditions that affect backbone solubility and the oxidation state of the thiol to successfully investigate the role that alpha-helical structure and disulfide bond formation play in protein stability. Our data indicate that covalent cross-linking helps to retain ATF5's helicity, which inhibits the formation of large aggregates. These studies have led to the identification of stabilizing conditions for ATF5, which will enable further study of the protein as a pharmaceutical target. Moreover, this work has general implications for analyzing stability of helical proteins in vitro as well as the specific atomic-level interactions in ATF5 that contribute to instability and self-association.

Dataset Information

Aggregation of Chameleon Peptides: Implications of ?-Helicity in Fibril Formation.

Publications

Aggregation of Chameleon Peptides: Implications of α-Helicity in Fibril Formation.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets