Volume 21 Issue 5, May 2014

Genome-wide association studies have identified genes encoding major histocompatibility (MHC) class II molecules as the single most important predisposing factor for autoimmunity. A new study provides atomic insight into how the antigen receptors of intestinal T cells recognize dietary gluten that drives celiac disease pathogenesis when bound to the MHC class II molecule HLA-DQ2.5, the major genetic risk factor of celiac disease.

The crystal structure of the FERM-SH2 region of Tyk2 in complex with the cytoplasmic tail of an interferon-α receptor provides a first view of specific JAK-receptor recognition and reveals a central role of the heretofore-marginalized JAK SH2 domain in recognizing the cytokine-receptor box2 motif.

A new report reveals how mammalian cells silence the DNA-damage response during mitosis to allow cell division to be completed in the presence of DNA lesions.

The crystal structure of the membrane insertase YidC reveals a hydrophilic groove in the cytoplasmic bilayer leaflet, suggesting a new mechanism of membrane-protein insertion.

Tail-anchor proteins are targeted post-translationally to the endoplasmic reticulum via the conserved GET pathway, in which the Get4–Get5 complex mediates delivery of substrates to Get3, the central targeting factor. The crystal structure of the ATP-bound Get3–Get4–Get5 complex and functional analyses reveal how Get4–Get5 primes Get3 for substrate loading.

How the four JAK kinases discriminate between different cytokine receptors is not well understood. The first crystal structure of a JAK kinase (TYK2) bound to a cytokine receptor (INFAR1) now exposes a multipoint interaction mode that involves an atypical phosphoindependent interaction between TYK2's SH2 domain and INFAR1's conserved box2 motif.

The genomic localization of Mediator in budding yeast is now assessed, revealing that Mediator remains associated with upstream activating sequences until it becomes transiently associated with core promoters during initiation. Phosphorylation of the CTD of Rpb1 at Ser5 by Kin28 releases Mediator prior to elongation.

CLC-type H⁺/Cl⁻ exchangers are known to be regulated by voltage and H⁺ and Cl⁻concentrations, but their gating mechanism remains poorly understood. New data now suggest that transport by the CLCs is regulated by two gates that are functionally linked through structural rearrangements outside of the ion-transport pathway.

It has long been thought that the catalytic RNAs of self-splicing group II introns and the spliceosome function by similar mechanisms. Now, a combination of genetic, cross-linking, and biochemical analyses of yeast U6 snRNA provide compelling evidence that spliceosomal RNAs form triplex structures similar to those used by group II introns to catalyze splicing.

LeuT is a Na⁺-coupled amino acid transporter that is similar in sequence and function to eukaryotic neurotransmitter/sodium symporters, which are active in reuptake of neurotransmitters from the synapse. Distance measurements between spin-label pairs are used to identify ligand-dependent structural transitions in LeuT.

A central event in celiac disease (CD) is the recognition by TCRs of gluten epitopes presented by specific HLAs, with HLA-DQ2 being associated with 95% of CD cases. The molecular basis for these interactions are now revealed by crystal structures of TCRs from individuals with CD in complex with wheat gliadin epitopes presented by HLA-DQ2.

Cyclic di-GMP (c-di-GMP) regulates a number of bacterial processes, including synthesis of cellulose during biofilm formation. The PilZ domain from bacterial cellulose synthase BcsA–BcsB senses c-di-GMP and activates the enzyme. Now crystal structures of BcsA–BcsB along with functional analysis reveal that binding of c-di-GMP releases a conserved gating loop to allow substrate to enter the active site.

5'-adenylated DNA adducts generated during nucleotide excision repair (NER) are removed by aprataxin to permit DNA end ligation. Now, structural and kinetic analyses reveal that NER enzymes DNA polymerase β and FEN1 can also excise these adducts and thus provide a 'backup' repair pathway for abasic sites.