Volume 18 Issue 2, February 2011

The interaction of autotaxin with its substrates leads to the production of lysophosphatidic acids (LPA), bioactive lipids with an emerging prominent role in inflammation and cancer. Two papers in this issue tell the previously unknown story of autotaxin, from substrate discrimination to highly efficient local delivery of LPA to target receptors.

Prdm14 is expressed in embryonic stem (ES) cells and germ cells. It is now shown that this transcription factor safeguards the stem cell state by preventing development of mouse ES cells into extraembryonic endoderm cells by repressing loci related to differentiation along this developmental pathway. This suggests that Pdrm14 is part of the network of factors that maintains the ES cell state in mice.

Binding of measles virus hemagglutinin (MVH) to its cellular receptors triggers the activation of the fusion protein. The conformational changes of MVH upon receptor binding are now examined by locking the dimers using disulfide bonds, or by pulling on appropriately positioned hexahistidine tags. The results indicate that the dimer interface is pulled apart after receptor binding by twisting of the MVH heads.

The measles virus hemagglutinin (MVH) promotes viral attachment to host cells via interaction with signaling lymphocyte activation molecule (SLAM). Now the crystal structure of MVH head domain in complex with the distal domain of SLAM, together with functional work, reveals the details of this interaction and explains the effectiveness of the currently used vaccine.

In Drosophila, upregulation of genes on the single male X chromosome to match that from the two female Xs depends upon the MSL complex. The structures of complexes of MSL subunits now give insight into how the MOF histone acetyltransferase and MSL3 interact with MSL1, indicating that the latter acts as a scaffold to bring the complex together.

BiP is an Hsp70 chaperone in the endoplasmic reticulum (ER) and is crucial for protein folding and quality control. Using single-molecule and ensemble FRET, the conformational cycle of BiP has now been defined. Movement of the lid domain of BiP allows this chaperone to discriminate between peptide and protein substrates.

Alternative splicing plays a major role in the generation of functional diversity but the underlying mechanisms remain poorly understood. In a comparative genome analysis of 73 arthropod species, spanning around 420 million years of evolution, Yongfeng and coworkers find built-in intronic elements that lead to mutual exclusive splicing. These elements are species- or clade-specific, but evolutionarily conserved at the secondary structure level.

Understanding the structural dynamics of ribosomal components is key to understanding translation. The Z-DNA– and Z-RNA–binding domain from the human RNA editing enzyme ADAR1-L is now shown to bind to specific regions of ribosomal RNAs affecting translation, suggesting that these regions might at least transiently form Z-RNA structure not observed in crystal structures.

Assembly of transcriptional repression complexes involves the recruitment of different proteins to SMRT or its homolog NCoR. Now structural and functional work reveal the tetrameric organization of the oligomerization domain of TBL1 and map its interactions with SMRT and GPS2. The authors propose a model for the architecture and assembly of the corepressor complex.

Bacteria have toxin-antitoxin systems that can trigger cell death upon different conditions, including phage infection. The recently identified type III TA system consists of an RNA endonuclease toxin and an RNA antitoxin, and the crystal structure of the complex is now presented.

Nucleotide excision repair is one of the main pathways for removal of damaged DNA. UvrA, which finds the damaged DNA, has broad specificity. The first crystal structure of UvrA in complex with DNA shows that the UvrA dimer does not contact the lesion directly but instead probes the conformation of the DNA around the modified residue.

The enzyme autotaxin (ATX) produces the lipid mediator LPA to stimulate cell migration and proliferation. The crystal structures of rat ATX, in its apo and inhibitor-bound forms, along with functional work, offer insight into substrate specificity and show that ATX interacts with integrins through one of its SMB domains.

:Autotaxin (ATX) is a secreted enzyme that produces lysophosphatidic acid (LPA), which in turn activates GPCRs to elicit cellular responses. The crystal structures of mouse ATX in its apo state and bound to different LPAs and functional work reveal a hydrophobic tunnel that could participate in direct delivery of the product to its cognate GPCRs.

Telomere protein RAP1 is found in organisms from yeast to mammals, but has different functions. Now the crystal structures of the RAP1 C-terminus (RCT) with its different interacting partners, together with functional analyses, reveal a conserved interaction module used by mammalian and fission yeast Rap1 to interact with TRF2 and Taz1, respectively, to mediate telomere protection. In contrast, in budding yeast this module recruits Sir3 to telomeres to mediate transcriptional silencing.

Serpins disable their target proteases by formation of an inhibitory complex in which the serpin experiences major structural reordering. How local unfolding allows the serpin to remodel its structure is now mapped by chemical probing. The evolution of functionally important conformationally labile regions has exposed serpins to a risk of aggregation, and indeed many serpinopathy-linked mutations map to the identified labile region.

XMRV is a retrovirus that has been linked to prostate cancer and chronic fatigue syndrome. The crystal structure of the XMRV protease differs from the structures of other retropepsins and instead resembles those of pepsin-like enzymes, suggesting that this protease may represent a distinct evolutionary branch of the aspartic proteases.

APOBEC1 is involved in conversion of a specific C to U in apolipoprotein B mRNA, a classic example of RNA editing. With a comparative RNA-Seq screen, numerous additional targets of APOBEC1 editing are found. Editing sites tend to be located in AU-rich regions of 3′ UTRs, and analysis identifies common features that prove predictive of additional targets.

microRNAs bind Argonaute proteins, guiding silencing of target mRNAs. CLIP-seq has now been used to map microRNA targets bound by Ago2 in a Dicer-dependent fashion in mouse ES cells. The study reveals that certain sets of transcripts, such as TGF-β signaling pathway components, tend to be targeted, and also identifies a G-rich motif in targets that may modulate regulation.

The interaction of solvent with protein has been a major unresolved and significant problem for decades. Now, NMR techniques characterize the hydration sites of ubiquitin encapsulated within reverse micelles. This approach reveals a clustering of water molecules with similar residence times, an observation that is generally not accessible by crystallographic analyses.