Volume 9 Issue 12, December 2013

Peptides fulfill many roles in immunology, yet none are more important than their role as immunogenic epitopes driving the adaptive immune response, our ultimate bulwark against infectious disease. Peptide epitopes are mediated primarily by their interaction with major histocompatibility complexes (T-cell epitopes) and antibodies (B-cell epitopes). As pathogen genomes continue to be revealed, both experimental and computational epitope mapping are becoming crucial tools in vaccine discovery^1,2. Immunoinformatics offers many tools, techniques and approaches for in silico epitope characterization, which is capable of greatly accelerating epitope design.

The Doc-Phd pair forms a bacterial toxin-antitoxin system, but the mechanism by which the Fic-family member Doc causes toxicity is not fully defined. New research shows that Doc unexpectedly functions as a kinase to phosphorylate elongation factor TU, thus inhibiting translation and leading to Doc-mediated growth arrest.

Allergic reactions to otherwise innocuous substances involve a complex interplay of molecular interactions—some strong, some weak. This study reveals a key role for low-affinity antibodies and thus a possible point of weakness that may be exploited for therapeutic intervention.

Noncanonical translation of prespliced mRNA provides physiological meaning to nuclear translation in generating antigenic peptide substrates for the endogenous major histocompatibility complex class I pathway.

A competitive inhibitor of the lipase ATGL reduces the availability of adipocyte fatty acids, causing insulin resistance in insulin-sensitive tissues.

A set of tetravalent antigens reveals that low-affinity interactions between an allergen epitope and IgE antibodies contribute to allergic responses through FcɛRI receptors on mast cells, and inhibiting these low-affinity epitopes prevents degranulation.

Identification of antibacterials and then their mechanism of action using metabolic suppression profiling uncovers inhibitors targeting glycine metabolism, PABA and biotin biosynthesis.

The bacterial glmS riboswitch is unique in that the bound glucosamine-6-phosphate ligand acts as a cofactor for ribozyme-mediated RNA cleavage. In vitro selection and crystallographic analysis reveal that three mutations convert glmS from a cofactor-dependent to a metal ion–dependent ribozyme.

The Doc-Phd toxin-antitoxin system inhibits bacterial translation via an unknown mechanism. Functional and structural analyses now show that Doc, which has an active site like AMPylating Fic proteins, actually works as a kinase, phosphorylating EF-Tu to block translation.

Spiran rings appear in numerous natural products, but the mechanism of their formation is not always clear. Reconstitution of the spirotryprostatin pathway now reveals that distinct biochemical mechanisms, one catalyzed by an enzyme from an unrelated pathway, lead to related spiran-containing structures.

Assembled helical maquettes have been used to mimic basic oxidoreductase activities, but the requisite design symmetry limited advanced functions. Construction of a single-chain protein now enables intra- and interprotein electron transfer and complex cofactor interactions at rates comparable to those of natural proteins.

Cyclic diadenosine monophosphate (c-di-AMP) is a newly identified nucleotide second messenger in bacteria. Though protein receptors for c-di-AMP are known, the ydaO riboswitch has now been validated as a physiological sensor of cellular c-di-AMP levels.

High-throughput screening systems that better mimic the physiological complexity of diseased tissues may aid the discovery of more efficacious compounds. A co-culture system that mimics the microenvironment of leukemia stem cells (LSCs) in bone marrow enables the discovery of compounds, including lovastatin, that selectively kill LSCs.

Peptides play a role in all aspects of the immunological responses to invading pathogens and tumor cells. The Review, Perspective and Commentary pieces in this issue explore the generation and molecular mechanisms of peptides and the considerations and strategies needed to harness them to treat disease.