Table of contents
January 2009, Volume 16 No 1 pp1-98
About the coverEditorial
Evolving the discussion - p1
doi:10.1038/nsmb0109-1
As we enter 2009 and celebrate the anniversaries associated with the birth of Darwin and publication of The Origin of Species, it's worth asking why there isn't greater public awareness of the increasing molecular evidence relevant to evolution and what can be done to address this.
Full Text - Evolving the discussion | PDF (225 KB) - Evolving the discussion
Meeting Report
The Hsp90 mosaic: a picture emerges - pp2 - 6
Matthias P Mayer, Chrisostomos Prodromou & Judith Frydman
doi:10.1038/nsmb0109-2
Hsp90s, molecular chaperones critically involved in many essential cellular processes, were the focus of a recent international conference held in Seeon, Germany. The scope of the conference ranged from structural and mechanistic insights all the way to medical applications.
Full Text - The Hsp90 mosaic: a picture emerges | PDF (338 KB) - The Hsp90 mosaic: a picture emerges
News and Views
Eye on RNA unwinding - pp7 - 8
David A Brow
doi:10.1038/nsmb0109-7
Biochemical studies on the spliceosomal helicase Brr2 reveal that it is activated by Prp8, the master regulator of the splicing cycle. Substitutions in Prp8 that cause retinal degeneration in humans block activation of Brr2, providing insight into the molecular pathology of retinitis pigmentosa.
Full Text - Eye on RNA unwinding | PDF (239 KB) - Eye on RNA unwinding
See also: Article by Maeder et al.
RNA stability: is it the endo' the world as we know it? - pp9 - 10
Jeffrey Wilusz
doi:10.1038/nsmb0109-9
Endonucleases have generally not been considered among the major factors in well-studied mRNA-decay and quality-control pathways in mammals and yeast. However, two important players in these pathways, the exosome and SMG6, have now been shown to contain functionally significant endonucleolytic activities.
Full Text - RNA stability: is it the endo' the world as we know it? | PDF (308 KB) - RNA stability: is it the endo' the world as we know it?
See also: Article by Eberle et al. | Article by Schaeffer et al.
Chromodomain-mediated spreading on active genes - pp11 - 13
Alison M Hosey & Marjorie Brand
doi:10.1038/nsmb0109-11
The formation of heterochromatin involves spreading of repressor proteins along large chromosomal domains. A new study reveals that the concept of spreading also holds true for establishing domains of active chromatin. More specifically, spreading of the Drosophila melanogaster male-specific lethal (MSL) activator complex, which is required for dosage compensation on the X chromosome, involves interaction between the MSL3 chromodomain and histone H3 methylated at lysine 36.
Full Text - Chromodomain-mediated spreading on active genes | PDF (922 KB) - Chromodomain-mediated spreading on active genes
Alternative splicing: regulation without regulators - pp13 - 15
Brenton R Graveley
doi:10.1038/nsmb0109-13
Alternative splicing is typically thought to be controlled by RNA binding proteins that modulate the activity of the spliceosome. A new study not only demonstrates that alternative splicing can be regulated without the involvement of auxiliary splicing factors, but also provides mechanistic insight into how this can occur.
Full Text - Alternative splicing: regulation without regulators | PDF (367 KB) - Alternative splicing: regulation without regulators
Research Highlights
Research highlights - p16
doi:10.1038/nsmb0109-16
Full Text - Research highlights | PDF (129 KB) - Research highlights
Articles
Histone H3 tail clipping regulates gene expression - pp17 - 22
Helena Santos-Rosa, Antonis Kirmizis, Christopher Nelson, Till Bartke, Nehme Saksouk, Jacques Cote & Tony Kouzarides
doi:10.1038/nsmb.1534
Nucleosome stability can influence gene expression and is regulated by nucleosome-positioning sequences, histone chaperones, remodeling complexes, post-translational modifications and histone variants. Now, histone H3 tail clipping has been added to the list. Kouzarides and co-workers have identified a serine endopeptidase in yeast that cleaves H3 after Ala21 and shows a preference for H3 tails with repressive modifications. In vivo, this occurs at the promoters of induced genes and precedes histone eviction when genes become fully active.
Abstract - | Full Text - Histone H3 tail clipping regulates gene expression | PDF (478 KB) - Histone H3 tail clipping regulates gene expression | Supplementary information
miR-29 miRNAs activate p53 by targeting p85
and CDC42 - pp23 - 29
Seong-Yeon Park, Jung Hyun Lee, Minju Ha, Jin-Wu Nam & V Narry Kim
doi:10.1038/nsmb.1533
The transcription factor and tumor suppressor p53 is central to many stress responses and is the target of multiple regulators. The regulatory subunit of PI3 kinase, p85
and CDC42 are now both found to be targets of the miR-29 microRNAs. As p85 and CDC42 are repressors of p53, these miRNAs indirectly activate p53 and thus apoptosis.
Abstract - | Full Text - miR-29 miRNAs activate p53 by targeting p85 and CDC42 | PDF (550 KB) - miR-29 miRNAs activate p53 by targeting p85 and CDC42 | Supplementary information
High-resolution structure of the open NaK channel - pp30 - 34
Amer Alam & Youxing Jiang
doi:10.1038/nsmb.1531
PDB code
3D view
Channel gating in tetrameric cation channels occurs as structural transitions that involve straightening and bending of inner helices at a conserved glycine residue. Structural representatives of these closed and opened states have come from crystal structure of KcsA and MthK, respectively. The structure of NaK in the open state, when combined with a previously determined structure of NaK in the closed state, allows the detailed analysis of channel gating within the same channel.
Abstract - | Full Text - High-resolution structure of the open NaK channel | PDF (774 KB) - High-resolution structure of the open NaK channel | Supplementary information
Structural analysis of ion selectivity in the NaK channel - pp35 - 41
Amer Alam & Youxing Jiang
doi:10.1038/nsmb.1537
Ion selectivity is as important to ion channel function as channel gating. Much of what is currently known about selectivity comes from structural studies of K+-selective channels. Detailed structural analysis of the ion binding sites in the NaK pore provides a first look at the geometry and ionic selectivity in a Na+-permeable channel and may provide a basis for understanding permeation through nonselective cation channels.
Abstract - | Full Text - Structural analysis of ion selectivity in the NaK channel | PDF (751 KB) - Structural analysis of ion selectivity in the NaK channel | Supplementary information
ATP-dependent unwinding of U4/U6 snRNAs by the Brr2 helicase requires the C terminus of Prp8 - pp42 - 48
Corina Maeder, Alan K Kutach & Christine Guthrie
doi:10.1038/nsmb.1535
Although a number of DExD/H-box family RNA-dependent ATPases are required in the spliceosome, their regulation is unclear. The Brr2-dependent unwinding of U4/U6 snRNAs, a key step in splicing, is now shown to be promoted in a purified system by the C-terminal region of Prp8, an enigmatic spliceosome component associated with a dominant form of retinitis pigmentosa.
Abstract - | Full Text - ATP-dependent unwinding of U4/U6 snRNAs by the Brr2 helicase requires the C terminus of Prp8 | PDF (550 KB) - ATP-dependent unwinding of U4/U6 snRNAs by the Brr2 helicase requires the C terminus of Prp8 | Supplementary information
See also: News and Views by Brow
SMG6 promotes endonucleolytic cleavage of nonsense mRNA in human cells - pp49 - 55
Andrea B Eberle, Søren Lykke-Andersen, Oliver Mühlemann & Torben Heick Jensen
doi:10.1038/nsmb.1530
Nonsense-mediated decay (NMD) is an mRNA surveillance process that targets transcripts containing a premature stop codon for degradation. Evidence now suggests that mammalian NMD involves an endonucleolytic cleavage that is mediated by human SMG6.
Abstract - | Full Text - SMG6 promotes endonucleolytic cleavage of nonsense mRNA in human cells | PDF (598 KB) - SMG6 promotes endonucleolytic cleavage of nonsense mRNA in human cells | Supplementary information
See also: News and Views by Wilusz | Article by Schaeffer et al.
The exosome contains domains with specific endoribonuclease, exoribonuclease and cytoplasmic mRNA decay activities - pp56 - 62
Daneen Schaeffer, Borislava Tsanova, Ana Barbas, Filipa Pereira Reis, Eeshita Ghosh Dastidar, Maya Sanchez-Rotunno, Cecília Maria Arraiano & Ambro van Hoof
doi:10.1038/nsmb.1528
The exosome is a large complex with cellular functions including exoribonucleolytic mRNA degradation and processing of a number of RNAs including small nuclear RNAs, small nucleolar RNAs and ribosomal RNAs. The yeast exosome is now shown to possess an unexpected endoribonucleolytic activity, and the essential Csl4 subunit is shown to contain a domain involved in mRNA decay. This suggests that particular domains in the complex have specialized roles.
Abstract - | Full Text - The exosome contains domains with specific endoribonuclease, exoribonuclease and cytoplasmic mRNA decay activities | PDF (670 KB) - The exosome contains domains with specific endoribonuclease, exoribonuclease and cytoplasmic mRNA decay activities | Supplementary information
See also: News and Views by Wilusz | Article by Eberle et al.
Rapid evolution of protein kinase PKR alters sensitivity to viral inhibitors - pp63 - 70
Stefan Rothenburg, Eun Joo Seo, James S Gibbs, Thomas E Dever & Katharina Dittmar
doi:10.1038/nsmb.1529
PKR responds to viral infection and shuts down translation through phosphorylation of eIF2. PKR is found to have rapidly evolved in comparison to other kinases targeting the same substrate across a broad range of vertebrate lineages. Some positively selected residues are found to confer resistance to poxviral inhibitors that mimic substrate. In addition, substituting a single residue in mouse PKR with the corresponding residue under positive selection in human PKR renders mouse PKR more resistant to K3L and vice versa, providing evidence for species-specific selection driven by beneficial mutations.
Abstract - | Full Text - Rapid evolution of protein kinase PKR alters sensitivity to viral inhibitors | PDF (891 KB) - Rapid evolution of protein kinase PKR alters sensitivity to viral inhibitors | Supplementary information
Inverse coupling in leak and voltage-activated K+ channel gates underlies distinct roles in electrical signaling - pp71 - 79
Yuval Ben-Abu, Yufeng Zhou, Noam Zilberberg & Ofer Yifrach
doi:10.1038/nsmb.1525
The negatively coupled movement of the activation and inactivation gates of Kv channels regulates ion flow across membranes in response to changes in membrane potential. Although they share a common pore design, the K2P leak channels are open at all potentials and are believed to act only through a slow inactivation gate. New data reveal that, similarly to the Kv channels, leak channels possess a constitutively open lower activation gate. Positive coupling between the two gates ensure constant leak currents across the membrane.
Abstract - | Full Text - Inverse coupling in leak and voltage-activated K+ channel gates underlies distinct roles in electrical signaling | PDF (837 KB) - Inverse coupling in leak and voltage-activated K+ channel gates underlies distinct roles in electrical signaling | Supplementary information
The mechanism of pentabromopseudilin inhibition of myosin motor activity - pp80 - 88
Roman Fedorov, Markus Böhl, Georgios Tsiavaliaris, Falk K Hartmann, Manuel H Taft, Petra Baruch, Bernhard Brenner, René Martin, Hans-Joachim Knölker, Herwig O Gutzeit & Dietmar J Manstein
doi:10.1038/nsmb.1542
Myosins have roles in many biological processes that go beyond muscle contraction and vesicle transport, including furrowing during cytokinesis, signal transduction and RNA polymerase I–dependent transcription. Studying these various complex processes will require the use of isoform-specific small molecules that alter motor activity. The marine natural product pentabromopseudilin is now shown to act as an allosteric effector of myosin function and potent inhibitor of vertebrate myosin-5a–dependent motor activity.
Abstract - | Full Text - The mechanism of pentabromopseudilin inhibition of myosin motor activity | PDF (835 KB) - The mechanism of pentabromopseudilin inhibition of myosin motor activity | Supplementary information
Brief Communications
Crystal structure of TIPE2 provides insights into immune homeostasis - pp89 - 90
Xu Zhang, Jiawei Wang, Chao Fan, Hubo Li, Honghong Sun, Shunyou Gong, Youhai H Chen & Yigong Shi
doi:10.1038/nsmb.1522
PDB code
3D view
TIPE2 is involved in immune homeostasis, and it has been assumed that it contained a death effector domain (DED). Now the crystal structure of TIPE2 reveals that it does not possess a DED, but instead has a previously uncharacterized fold, with a large central cavity that might accommodate a ligand.
Abstract - | Full Text - Crystal structure of TIPE2 provides insights into immune homeostasis | PDF (363 KB) - Crystal structure of TIPE2 provides insights into immune homeostasis | Supplementary information
An atypical RNA polymerase involved in RNA silencing shares small subunits with RNA polymerase II - pp91 - 93
Linfeng Huang, Alexandra M E Jones, Iain Searle, Kanu Patel, Hannes Vogler, Nina C Hubner & David C Baulcombe
doi:10.1038/nsmb.1539
Plants contain atypical RNA polymerases that have been implicated in RNA silencing. An analysis of RNA polymerase V composition now reveals that it unexpectedly shares some, but not all, subunits found in RNA polymerase II, indicating that it may be a derived version of this polymerase complex. Additional subunits are also identified and implicated in RNA-mediated silencing.
Abstract - | Full Text - An atypical RNA polymerase involved in RNA silencing shares small subunits with RNA polymerase II | PDF (349 KB) - An atypical RNA polymerase involved in RNA silencing shares small subunits with RNA polymerase II | Supplementary information
Structure of the motor subunit of type I restriction-modification complex EcoR124I - pp94 - 95
Mikalai Lapkouski, Santosh Panjikar, Pavel Janscak, Ivana Kuta Smatanova, Jannette Carey, Rüdiger Ettrich & Eva Csefalvay
doi:10.1038/nsmb.1523
PDB code
3D view
Type I restriction-modification enzymes recognize a target sequence and translocate DNA from both sides while remaining stationary, creating supercoiled loops and cleaving at nonspecific sites several kilobases away. The crystal structure of the motor subunit of EcoR124I is now solved, providing insight into these complex machines.
Abstract - | Full Text - Structure of the motor subunit of type I restriction-modification complex EcoR124I | PDF (583 KB) - Structure of the motor subunit of type I restriction-modification complex EcoR124I | Supplementary information
Ligands bind to Sortilin in the tunnel of a ten-bladed 
-propeller domain - pp96 - 98
Esben M Quistgaard, Peder Madsen, Morten K Grøftehauge, Poul Nissen, Claus M Petersen & Søren S Thirup
doi:10.1038/nsmb.1543
PDB code
3D view
Sortilin is a neuronal receptor involved in sorting and signal transduction. The crystal structure of the mature Sortilin ectodomain bound to one of its ligands, neurotensin, reveals a binding tunnel formed by the Sortilin 
-propeller domain. Combined with binding and mutagenesis studies, the findings suggest that Sortilin substrates compete for access to the tunnel so that only one ligand binds at a time.
Abstract - | Full Text - Ligands bind to Sortilin in the tunnel of a ten-bladed -propeller domain | PDF (361 KB) - Ligands bind to Sortilin in the tunnel of a ten-bladed -propeller domain | Supplementary information
