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The parathyroid hormone (PTH) type 1 receptor (PTHR) is a class B G protein–coupled receptor (GPCR) that regulates mineral ion, vitamin D, and bone homeostasis. Activation of the PTHR by PTH induces both transient cell surface and sustained endosomal cAMP production. To address whether the spatial (location) or temporal (duration) dimension of PTHR-induced cAMP encodes distinct biological outcomes, we engineered a biased PTHR ligand (PTH7d) that elicits cAMP production at the plasma membrane but not at endosomes. PTH7d stabilized a unique active PTHR conformation that mediated sustained cAMP signaling at the plasma membrane due to impaired β-arrestin coupling to the receptor. Experiments in cells and mice revealed that sustained cAMP production by cell surface PTHR failed to mimic the pharmacological effects of sustained endosomal cAMP production on the abundance of the rate-limiting hydroxylase catalyzing the formation of active vitamin D, as well as increases in circulating active vitamin D and Ca2+ and in bone formation in mice. Thus, similar amounts of cAMP generated by PTHR for similar lengths of time in different cellular locations, plasma membrane and endosomes, mediate distinct physiological responses. These results unveil subcellular signaling location as a means to achieve specificity in PTHR-mediated biological outcomes and raise the prospect of rational drug design based upon spatiotemporal manipulation of GPCR signaling.

Glyoxylic acid and glycine are widely considered to have been important prebiotic building blocks. Several mechanistic routes have been previously examined for conversion of glyoxylic acid to glycine. Here we provide evidence for a new mechanistic path. Glycine is spontaneously formed from glyoxylic acid in ammonium‐rich aqueous solutions at neutral pH; oxamic acid is generated as well. Hydride transfer from the glyoxylate‐derived hemiaminal to the corresponding iminium ion appears to underlie this transformation. This proposed mechanism parallels the well‐known Cannizzaro reaction mechanism, which leads us to suggest the designation "aza‐Cannizzaro reaction." This discovery offers a new perspective on prebiotic nitrogen incorporation because glycine can be a source of nitrogen for more complex molecules, including other α‐amino acids. [ABSTRACT FROM AUTHOR]

Novel synthetic mimics of antimicrobial peptides have been developed to exhibit structural properties and antimicrobial activity similar to those of natural antimicrobial peptides (AMPs) of the innate immune system. These molecules have a number of potential advantages over conventional antibiotics, including reduced bacterial resistance, cost-effective preparation, and customizable designs. In this study, we investigate a family of nylon-3 polymer-based antimicrobials. By combining vesicle dye leakage, bacterial permeation, and bactericidal assays with small-angle X-ray scattering (SAXS), we find that these polymers are capable of two interdependent mechanisms of action: permeation of bacterial membranes and binding to intracellular targets such as DNA, with the latter necessarily dependent on the former. We systemically examine polymer-induced membrane deformation modes across a range of lipid compositions that mimic both bacteria and mammalian cell membranes. The results show that the polymers' ability to generate negative Gaussian curvature (NGC), a topological requirement for membrane permeation and cellular entry, in model Escherichia coli membranes correlates with their ability to permeate membranes without complete membrane disruption and kill E. coli cells. Our findings suggest that these polymers operate with a concentration-dependent mechanism of action: at low concentrations permeation and DNA binding occur without membrane disruption, while at high concentrations complete disruption of the membrane occurs. This article is part of a Special Issue entitled: Interfacially Active Peptides and Proteins. Guest Editors: William C. Wimley and Kalina Hristova.

Chemical force microscopy measurements show that the immobilization of specific cationic groups near non-polar domains produces pronounced changes in the domains' hydrophobic interaction strengths: charged ammonium groups double interaction strengths, whereas guanidinium groups eliminate measurable interactions. Immobilized ions tune hydrophobic interactions The so-called hydrophobic effect is the basis of many well-known interfacial, colloidal and biophysical phenomena, including the immiscibility of oil and water and the beading of water on nonpolar surfaces. It arises as a result of the structuring of water near non-polar surfaces, but although we understand hydrophobic interactions in simple systems, most biologically and technologically relevant structures are another matter. These more complex systems are characterized by intricate patterns of non-polar, polar and charged domains in close proximity. Derek Ma and colleagues now show that cations placed near a non-polar domain strongly modulate its hydrophobic interactions, with some cations doubling the strength of the interactions, whereas others eliminate it. The findings imply that in addition to established strategies for optimizing molecular recognition or self-assembly, judicious placing of charged groups near hydrophobic domains can also be used to tune the hydrophobic forces driving such processes. The structure of water near non-polar molecular fragments or surfaces mediates the hydrophobic interactions that underlie a broad range of interfacial, colloidal and biophysical phenomena.sup.1,2,3,4. Substantial progress over the past decade has improved our understanding of hydrophobic interactions in simple model systems.sup.1,5,6,7,8,9,10, but most biologically and technologically relevant structures contain non-polar domains in close proximity to polar and charged functional groups. Theories and simulations exploring such nanometre-scale chemical heterogeneity find it can have an important effect.sup.8,10,11,12, but the influence of this heterogeneity on hydrophobic interactions has not been tested experimentally. Here we report chemical force microscopy measurements on alkyl-functionalized surfaces that reveal a dramatic change in the surfaces' hydrophobic interaction strengths on co-immobilization of amine or guanidine groups. Protonation of amine groups doubles the strength of hydrophobic interactions, and guanidinium groups eliminate measurable hydrophobic interactions in all pH ranges investigated. We see these divergent effects of proximally immobilized cations also in single-molecule measurements on conformationally stable [beta]-peptides with non-polar subunits located one nanometre from either amine- or guanidine-bearing subunits. Our results demonstrate the importance of nanometre-scale chemical heterogeneity, with hydrophobicity not an intrinsic property of any given non-polar domain but strongly modulated by functional groups located as far away as one nanometre. The judicious placing of charged groups near hydrophobic domains thus provides a strategy for tuning hydrophobic driving forces to optimize molecular recognition or self-assembly processes., Author(s): C. Derek Ma [sup.1] , Chenxuan Wang [sup.1] [sup.2] , Claribel Acevedo-Vélez [sup.1] , Samuel H. Gellman [sup.2] , Nicholas L. Abbott [sup.1] Author Affiliations: (1) Department of Chemical [...]