Biology subjects

Mertz, B.

Publications and source records attributed to Mertz, B..

3 recordsLinked to original sources

bioRxiv2024

Blocking the ability of huntingtin to bind membranes: a therapeutic strategy for Huntingtons disease

The ordered aggregation of proteins into amyloid fibrils is a hallmark of numerous neurodegenerative diseases. A common strategy in developing therapeutics for amyloid-based diseases relies on preventing or manipulating the aggregation process. However, many amyloid-forming proteins and their aggregates bind and damage organelle and cellular membranes. As such, blocking the ability of these proteins from directly interacting with membranes represents a unique therapeutic strategy. Using a mutant huntingtin (htt) protein associated with Huntingtons disease (HD) as a model system, the viability of this strategy was evaluated. Screening over 1200 compounds for their ability to block htt binding to lipid vesicles, two compounds, Ro90-7501 (Ro) and Benzamil (Ben), were identified and validated. Despite directly interacting with htt, neither compound prevented fibril formation. Molecular dynamics simulations suggested each compound has a unique mechanism of action, consistent with experimental data. Importantly, both compounds ameliorated phenotype in a C. elegans model of HD.

biophysics↗

bioRxiv2020

Oligomerization of the Human Adenosine A2A Receptor Is Driven by the Intrinsically Disordered C-Terminus

G protein-coupled receptors (GPCRs) have long been shown to exist as oligomers with functional properties distinct from those of the monomeric counterparts, but the driving factors of GPCR oligomerization remain relatively unexplored. In this study, we focus on the human adenosine A2A receptor (A2AR), a model GPCR that forms oligomers both in vitro and in vivo. Combining experimental and computational approaches, we discover that the intrinsically disordered C-terminus of A2AR drives the homo-oligomerization of the receptor. The formation of A2AR oligomers declines progressively and systematically with the shortening of the C-terminus. Multiple interaction sites and types are responsible for A2AR oligomerization, including disulfide linkages, hydrogen bonds, electrostatic interactions, and hydrophobic interactions. These interactions are enhanced by depletion interactions along the C-terminus, forming a tunable network of bonds that allow A2AR oligomers to adopt multiple interfaces. This study uncovers the disordered C-terminus as a prominent driving factor for the oligomerization of a GPCR, offering important guidance for structure-function studies of A2AR and other GPCRs.

biophysics↗

bioRxiv2018

Cooperative Non-bonded Forces Control Membrane Binding of the pH-Low Insertion Peptide pHLIP

Peptides with the ability to bind and insert into the cell membrane have immense potential in biomedical applications. pH (Low) Insertion Peptide (pHLIP), a water-soluble polypeptide derived from helix C of bacteriorhodopsin, can insert into a membrane at acidic pH to form a stable transmembrane -helix. The insertion process takes place in three stages: pHLIP is unstructured and soluble in water at neutral pH (state I), unstructured and bound to the surface of a membrane at neutral pH (state II), and inserted into the membrane as an -helix at low pH (state III). Using molecular dynamics (MD) simulations, we have modeled state II of pHLIP and a fast-folding variant of pHLIP, in which each peptide is bound to a 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) bilayer surface. Our results provide strong support for recently published spectroscopic studies, namely that pHLIP preferentially binds to the bilayer surface as a function of location of anionic amino acids and that backbone dehydration occurs upon binding. Unexpectedly, we also observed several instances of segments of pHLIP folding into a stable helical turn. Our results provide a molecular level of detail that is essential to providing new insights into pHLIP function and to facilitate design of variants with improved cell-penetrating capabilities.

biophysics↗