Volume 17 Issue 2, February 2010

γ-secretase cleaves multiple substrates with essential roles from development to neurodegeneration, and its aberrant processing underlies human disorders including Alzheimer's disease (AD). Tian et al. now identify a domain in the β-amyloid precursor protein (APP) that inhibits γ-secretase activity and show that certain familial AD–linked APP mutations within this domain impair this inhibition, resulting in increased β-amyloid generation. The study thus reveals a novel mechanism whereby γ-secretase's activity is influenced by its own substrate.

Myotonic dystrophy is caused by expanded CTG repeats, and the expression of these repeats as RNA leads to the sequestration of the splicing factor muscleblind-like (MBNL1) to the CUG RNA. Two mouse models for myotonic dystrophy—mice expressing expanded CUG repeats and mice lacking functional MBNL1—now reveal ∼100 new mis-splicing events and a new class of aberrantly regulated mRNAs.

Argonaute family members are key effectors of small RNA function. Predicted structural analogies to allosterically-regulated bacterial ligand-binding proteins, followed by biochemical analysis of the binding properties of Argonautes, now indicate functional allostery between two distinct binding sites that would promote a functional outcome when both a miRNA and capped mRNA are present.

Among the mutations in the amyloid precursor protein (APP) involved in familial Alzheimer's disease is the so-called Flemish mutation (A21G). Now a biochemical study of this mutation reveals the existence of a domain in APP that binds to an allosterica site in the γ-secretase complex and inhibits the enzymatic activity leading to the production of amyloidogenic peptide Aβ.

Alcohol dehydrogenase (ALDH2) is involved in metabolising ethanol. A single point mutation leads to Asian alcohol-induced flushing syndrome and is linked to increased cardiac damage following a heart attack. The small molecule Alda-1 restores normal activity to the mutant, and structures of Alda-1 bound to mutant ALDH2 and the wild type now explain this effect.

The protein VP35 from Ebola virus contributes to immune evasion by antagonizing interferon signaling pathways. Now the crystal structure of the interferon inhibitory domain of VP35 bound to dsRNA indicates that VP35 sequesters the dsRNA ends, preventing them from being sensed by RIG-I-like receptors and inhibiting immune responses.

MicroRNAs are small RNAs involved in regulation of cognate mRNAs, but predicting their exact targets has been difficult. Using a cross-linking immunoprecipitation technique, a comprehensive examination of endogenous mRNA target sites associated with the C. elegans Argonaute family member ALG-1 is now presented.

The Sec3 subunit of the yeast exocyst complex tethers secretory vesicles to the plasma membrane for exocytosis through interactions with a small GTPase and PtdIns(4,5)P2 in the target membrane. A new study describes the crystal structure of the N-terminal Rho1/Cdc42- and PtdIns(4,5)P2-binding domain of Sec3 in complex with Rho1.

Myotonic dystrophy is a CUG repeat expansion disease and mice deficient in MBNL1, an RNA binding protein, show many characteristics of the disease. Comparison of gene expression profiles of two mouse models of the disease reveals that CUG repeat expansions have two effects – loss of Mbnl1 function that leads to altered splicing and loss of an as yet unknown function that disrupts extracellular matrix protein mRNA regulation.

CDK8 is a kinase found in some Mediator complexes and has been implicated in oncogenesis. Now it is shown to be a positive regulator of transcription elongation at immediate early serum response genes, regulating recruitment of elongation factors including P-TEFb.

The yeast telomerase subunit Est1p has been implicated in recruitment of the telomerase complex to telomeres via its interaction with Cdc13p, but genetic data have pointed to an additional role for Est1p in telomere maintenance. Now Est1p is shown to convert G-rich telomeric DNA into G-quadruplex structures in vitro, and this activity is essential for telomere length maintenance in vivo.

Some viral proteins involved in interaction with the host cell surface adopt a very rigid and stable triple–β-helix fold. In order to attain this complex fold, these proteins contain an intramolecular chaperone domain that is auto-cleaved after assembly. Now structural work on two such chaperone domains indicates how they can promote correct folding of the β-helices.

Reversible phosphorylation plays a key role in splicing. Phosphorylation of two splicing components, PRP6 and PRP31, is now shown to be mediated by PRP4. This activity is involved in promoting the stable association of the triple-snRNP to form B complexes, indicating how this kinase promotes building of a stable, functional spliceosome.

APOBEC3 cytidine deaminases have been implicated in restriction of retroviruses and retrotransposons in mammalian cells. Now human APOBEC3A is shown to be upregulated by interferon and to catalyze the deamination of foreign double-stranded DNA transfected into primary cells or cell lines, with no detectable effect on genomic DNA.

In voltage-gated sodium channels, a voltage-sensor domain communicates with the pore gate regions, but the details of this process remain unclear. Now the electromechanical coupling in a Na+ channel is probed by tryptophane scanning mutagenesis, together with structural modeling, with the results indicating a crucial role for the hinge regions.

GW182 has been implicated in the effector steps of microRNA-mediated repression and recently shown to interact with the Poly(A) binding protein C-terminal domain (PABPC1). The structure of PABPC1 in complex with a human GW182 paralog peptide, now gives insight into the interactions needed to elicit target deadenylation.

The solution structures of the two PAR-binding zinc finger (PBZ) modules from APLF, a human protein putatively involved in DNA damage response, are now presented. Together with binding studies with PAR fragments and mutagenesis, the work sheds light on PAR recognition by PBZ modules.

Nonsense-mediated mRNA decay (NMD) recognizes and degrades mRNAs with premature termination codons. In yeast, this occurs by decapping followed by 5' to 3' exonucleolytic digestion. New work shows that substrates of NMD pathway are targeted for decapping while the mRNA is associated with polyribosomes. These findings are in contrast to previous work which suggested that NMD occurs in ribosome-free P bodies but are consistent with recent work showing that 'normal' mRNAs are decapped co-translationally.

Respiratory syncytial virus (RSV) is a highly contagious illness in young children. The structure of antibody drug motavizumab in complex with a 24-residue peptide corresponding to its epitope on RSV-fusion glycoprotein suggests why it is more potent than its predecessor, palivizumab (Synagis).

Nucleosome occupancy can affect the accessibility of DNA to other factors. A genome-wide map of nucleosomes in Schizosaccharomyces pombe is now presented. Comparisons to published Saccharomyces cerevisiae maps reveal species-specific differences arguing for evolutionary plasticity of nucleosome positioning mechanisms.