| 11561772 | Understanding transport by the major facilitator superfamily (MFS): structures pave the way. | Quistgaard EM, etal., Nat Rev Mol Cell Biol. 2016 Feb;17(2):123-32. doi: 10.1038/nrm.2015.25. Epub 2016 Jan 13. | Members of the major facilitator superfamily (MFS) of transport proteins are essential for the movement of a wide range of substrates across biomembranes. As this transport requires a series of conformational changes, structures of MFS transporters captured in different conformational states are ne eded to decipher the transport mechanism. Recently, a large number of MFS transporter structures have been determined, which has provided us with an unprecedented opportunity to understand general aspects of the transport mechanism. We propose an updated model for the conformational cycle of MFS transporters, the 'clamp-and-switch model', and discuss the role of so-called 'gating residues' and the substrate in modulating these conformational changes. | 26758938 | 2016-11-01 |
| 10412665 | Mitochondrial protein import: from proteomics to functional mechanisms. | Schmidt O, etal., Nat Rev Mol Cell Biol. 2010 Sep;11(9):655-67. doi: 10.1038/nrm2959. | Mitochondria contain approximately 1,000 different proteins, most of which are imported from the cytosol. Two import pathways that direct proteins into the mitochondrial inner membrane and matrix have been known for many years. The identification of numerous new transport components in recent proteo mic studies has led to novel mechanistic insight into these pathways and the discovery of new import pathways into the outer membrane and intermembrane space. Protein translocases do not function as independent units but are integrated into dynamic networks and are connected to machineries that function in bioenergetics, mitochondrial morphology and coupling to the endoplasmic reticulum. | 20729931 | 2010-11-01 |
| 10044021 | mRNA helicases: the tacticians of translational control. | Parsyan A, etal., Nat Rev Mol Cell Biol. 2011 Apr;12(4):235-45. doi: 10.1038/nrm3083. | The translation initiation step in eukaryotes is highly regulated and rate-limiting. During this process, the 40S ribosomal subunit is usually recruited to the 5' terminus of the mRNA. It then migrates towards the initiation codon, where it is joined by the 60S ribosomal subunit to form the 80S init iation complex. Secondary structures in the 5' untranslated region (UTR) can impede binding and movement of the 40S ribosome. The canonical eukaryotic translation initiation factor eIF4A (also known as DDX2), together with its accessory proteins eIF4B and eIF4H, is thought to act as a helicase that unwinds secondary structures in the mRNA 5' UTR. Growing evidence suggests that other helicases are also important for translation initiation and may promote the scanning processivity of the 40S subunit, synergize with eIF4A to 'melt' secondary structures or facilitate translation of a subset of mRNAs. | 21427765 | 2011-06-01 |
| 9585681 | New insights into nucleosome and chromatin structure: an ordered state or a disordered affair? | Luger K, etal., Nat Rev Mol Cell Biol. 2012 Jun 22;13(7):436-47. doi: 10.1038/nrm3382. | The compaction of genomic DNA into chromatin has profound implications for the regulation of key processes such as transcription, replication and DNA repair. Nucleosomes, the repeating building blocks of chromatin, vary in the composition of their histone protein components. This is the result of t he incorporation of variant histones and post-translational modifications of histone amino acid side chains. The resulting changes in nucleosome structure, stability and dynamics affect the compaction of nucleosomal arrays into higher-order structures. It is becoming clear that chromatin structures are not nearly as uniform and regular as previously assumed. This implies that chromatin structure must also be viewed in the context of specific biological functions. | 22722606 | 2012-09-01 |
| 7204692 | STIM proteins: dynamic calcium signal transducers. | Soboloff J, etal., Nat Rev Mol Cell Biol. 2012 Sep;13(9):549-65. doi: 10.1038/nrm3414. | Stromal interaction molecule (STIM) proteins function in cells as dynamic coordinators of cellular calcium (Ca(2+)) signals. Spanning the endoplasmic reticulum (ER) membrane, they sense tiny changes in the levels of Ca(2+) stored within the ER lumen. As ER Ca(2+) is released to generate primary Ca(2 +) signals, STIM proteins undergo an intricate activation reaction and rapidly translocate into junctions formed between the ER and the plasma membrane. There, STIM proteins tether and activate the highly Ca(2+)-selective Orai channels to mediate finely controlled Ca(2+) signals and to homeostatically balance cellular Ca(2+). Details are emerging on the remarkable organization within these STIM-induced junctional microdomains and the identification of new regulators and alternative target proteins for STIM. | 22914293 | 2012-12-01 |
| 6767570 | AMPK: a nutrient and energy sensor that maintains energy homeostasis. | Hardie DG, etal., Nat Rev Mol Cell Biol. 2012 Mar 22;13(4):251-62. doi: 10.1038/nrm3311. | AMP-activated protein kinase (AMPK) is a crucial cellular energy sensor. Once activated by falling energy status, it promotes ATP production by increasing the activity or expression of proteins involved in catabolism while conserving ATP by switching off biosynthetic pathways. AMPK also regulates m etabolic energy balance at the whole-body level. For example, it mediates the effects of agents acting on the hypothalamus that promote feeding and entrains circadian rhythms of metabolism and feeding behaviour. Finally, recent studies reveal that AMPK conserves ATP levels through the regulation of processes other than metabolism, such as the cell cycle and neuronal membrane excitability. | 22436748 | 2012-07-01 |
| 9686092 | A day in the life of the spliceosome. | Matera AG and Wang Z, Nat Rev Mol Cell Biol. 2014 Feb;15(2):108-21. doi: 10.1038/nrm3742. | One of the most amazing findings in molecular biology was the discovery that eukaryotic genes are discontinuous, with coding DNA being interrupted by stretches of non-coding sequence. The subsequent realization that the intervening regions are removed from pre-mRNA transcripts via the activity of a common set of small nuclear RNAs (snRNAs), which assemble together with associated proteins into a complex known as the spliceosome, was equally surprising. How do cells coordinate the assembly of this molecular machine? And how does the spliceosome accurately recognize exons and introns to carry out the splicing reaction? Insights into these questions have been gained by studying the life cycle of spliceosomal snRNAs from their transcription, nuclear export and re-import to their dynamic assembly into the spliceosome. This assembly process can also affect the regulation of alternative splicing and has implications for human disease. | 24452469 | 2014-01-01 |
| 10402127 | Mechanisms of mitophagy. | Youle RJ and Narendra DP, Nat Rev Mol Cell Biol. 2011 Jan;12(1):9-14. doi: 10.1038/nrm3028. | Autophagy not only recycles intracellular components to compensate for nutrient deprivation but also selectively eliminates organelles to regulate their number and maintain quality control. Mitophagy, the specific autophagic elimination of mitochondria, has been identified in yeast, mediated by auto phagy-related 32 (Atg32), and in mammals during red blood cell differentiation, mediated by NIP3-like protein X (NIX; also known as BNIP3L). Moreover, mitophagy is regulated in many metazoan cell types by parkin and PTEN-induced putative kinase protein 1 (PINK1), and mutations in the genes encoding these proteins have been linked to forms of Parkinson's disease. | 21179058 | 2011-01-01 |
| 7246920 | TFIIH: when transcription met DNA repair. | Compe E and Egly JM, Nat Rev Mol Cell Biol. 2012 May 10;13(6):343-54. doi: 10.1038/nrm3350. | The transcription initiation factor TFIIH is a remarkable protein complex that has a fundamental role in the transcription of protein-coding genes as well as during the DNA nucleotide excision repair pathway. The detailed understanding of how TFIIH functions to coordinate these two processes is als o providing an explanation for the phenotypes observed in patients who bear mutations in some of the TFIIH subunits. In this way, studies of TFIIH have revealed tight molecular connections between transcription and DNA repair and have helped to define the concept of 'transcription diseases'. | 22572993 | 2012-06-01 |
| 7242698 | H(2)S signalling through protein sulfhydration and beyond. | Paul BD and Snyder SH, Nat Rev Mol Cell Biol. 2012 Jul 11;13(8):499-507. doi: 10.1038/nrm3391. | Hydrogen sulfide (H(2)S) has recently emerged as a mammalian gaseous messenger molecule, akin to nitric oxide and carbon monoxide. H(2)S is predominantly formed from Cys or its derivatives by the enzymes cystathionine beta-synthase and cystathionine gamma-lyase. One of the mechanisms by which H(2)S signals is by sulfhydration of reactive Cys residues in target proteins. Although analogous to protein nitrosylation, sulfhydration is substantially more prevalent and usually increases the catalytic activity of targeted proteins. Physiological actions of sulfhydration include the regulation of inflammation and endoplasmic reticulum stress signalling as well as of vascular tension. | 22781905 | 2012-04-01 |
| 9831133 | Nuclear pore complex composition: a new regulator of tissue-specific and developmental functions. | Raices M and D'Angelo MA, Nat Rev Mol Cell Biol. 2012 Nov;13(11):687-99. doi: 10.1038/nrm3461. | Nuclear pore complexes (NPCs) are multiprotein aqueous channels that penetrate the nuclear envelope connecting the nucleus and the cytoplasm. NPCs consist of multiple copies of roughly 30 different proteins known as nucleoporins (NUPs). Due to their essential role in controlling nucleocytoplasmic tr ansport, NPCs have traditionally been considered as structures of ubiquitous composition. The overall structure of the NPC is indeed conserved in all cells, but new evidence suggests that the protein composition of NPCs varies among cell types and tissues. Moreover, mutations in various nucleoporins result in tissue-specific diseases. These findings point towards a heterogeneity in NPC composition and function. This unexpected heterogeneity suggests that cells use a combination of different nucleoporins to assemble NPCs with distinct properties and specialized functions. | 23090414 | 2012-02-01 |
| 7365105 | The complex world of WNT receptor signalling. | Niehrs C Nat Rev Mol Cell Biol. 2012 Dec;13(12):767-79. doi: 10.1038/nrm3470. Epub 2012 Nov 15. | 30 years after the identification of WNTs, their signal transduction has become increasingly complex, with the discovery of more than 15 receptors and co-receptors in seven protein families. The recent discovery of three receptor classes for the R-spondin family of WNT agonists further adds to this complexity. What emerges is an intricate network of receptors that form higher-order ligand-receptor complexes routing downstream signalling. These are regulated both extracellularly by agonists such as R-spondin and intracellularly by post-translational modifications such as phosphorylation, proteolytic processing and endocytosis. | 23151663 | 2012-10-01 |
| 9479186 | Trithorax group proteins: switching genes on and keeping them active. | Schuettengruber B, etal., Nat Rev Mol Cell Biol. 2011 Nov 23;12(12):799-814. doi: 10.1038/nrm3230. | Cellular memory is provided by two counteracting groups of chromatin proteins termed Trithorax group (TrxG) and Polycomb group (PcG) proteins. TrxG proteins activate transcription and are perhaps best known because of the involvement of the TrxG protein MLL in leukaemia. However, in terms of molecul ar analysis, they have lived in the shadow of their more famous counterparts, the PcG proteins. Recent advances have improved our understanding of TrxG protein function and demonstrated that the heterogeneous group of TrxG proteins is of critical importance in the epigenetic regulation of the cell cycle, senescence, DNA damage and stem cell biology. | 22108599 | 2011-08-01 |
| 9681740 | The super elongation complex (SEC) family in transcriptional control. | Luo Z, etal., Nat Rev Mol Cell Biol. 2012 Sep;13(9):543-7. doi: 10.1038/nrm3417. Epub 2012 Aug 16. | The super elongation complex (SEC) consists of the RNA polymerase II (Pol II) elongation factors eleven-nineteen Lys-rich leukaemia (ELL) proteins, positive transcription elongation factor b (P-TEFb) and several frequent mixed lineage leukaemia (MLL) translocation partners. It is one of the most act ive P-TEFb-containing complexes required for rapid transcriptional induction in the presence or absence of paused Pol II. The SEC was found to regulate the transcriptional elongation checkpoint control (TECC) stage of transcription, and misregulation of this stage is associated with cancer pathogenesis. Recent studies have shown that the SEC belongs to a larger family of SEC-like complexes, which includes SEC-L2 and SEC-L3, each with distinct gene target specificities. | 22895430 | 2012-12-01 |
| 9686381 | Alternative splicing: a pivotal step between eukaryotic transcription and translation. | Kornblihtt AR, etal., Nat Rev Mol Cell Biol. 2013 Mar;14(3):153-65. doi: 10.1038/nrm3525. Epub 2013 Feb 6. | Alternative splicing was discovered simultaneously with splicing over three decades ago. Since then, an enormous body of evidence has demonstrated the prevalence of alternative splicing in multicellular eukaryotes, its key roles in determining tissue- and species-specific differentiation patterns, the multiple post- and co-transcriptional regulatory mechanisms that control it, and its causal role in hereditary disease and cancer. The emerging evidence places alternative splicing in a central position in the flow of eukaryotic genetic information, between transcription and translation, in that it can respond not only to various signalling pathways that target the splicing machinery but also to transcription factors and chromatin structure. | 23385723 | 2013-02-01 |
| 8661237 | Double-strand break repair: 53BP1 comes into focus. | Panier S and Boulton SJ, Nat Rev Mol Cell Biol. 2014 Jan;15(1):7-18. doi: 10.1038/nrm3719. Epub 2013 Dec 11. | DNA double-strand break (DSB) signalling and repair is crucial to preserve genomic integrity and maintain cellular homeostasis. p53-binding protein 1 (53BP1) is an important regulator of the cellular response to DSBs that promotes the end-joining of distal DNA ends, which is induced during V(D)J an d class switch recombination as well as during the fusion of deprotected telomeres. New insights have been gained into the mechanisms underlying the recruitment of 53BP1 to damaged chromatin and how 53BP1 promotes non-homologous end-joining-mediated DSB repair while preventing homologous recombination. From these studies, a model is emerging in which 53BP1 recruitment requires the direct recognition of a DSB-specific histone code and its influence on pathway choice is mediated by mutual antagonism with breast cancer 1 (BRCA1). | 24326623 | 2014-06-01 |
| 9479182 | Histone variants--ancient wrap artists of the epigenome. | Talbert PB and Henikoff S, Nat Rev Mol Cell Biol. 2010 Apr;11(4):264-75. doi: 10.1038/nrm2861. Epub 2010 Mar 3. | Histones wrap DNA to form nucleosome particles that compact eukaryotic genomes. Variant histones have evolved crucial roles in chromosome segregation, transcriptional regulation, DNA repair, sperm packaging and other processes. 'Universal' histone variants emerged early in eukaryotic evolution and w ere later displaced for bulk packaging roles by the canonical histones (H2A, H2B, H3 and H4), the synthesis of which is coupled to DNA replication. Further specializations of histone variants have evolved in some lineages to perform additional tasks. Differences among histone variants in their stability, DNA wrapping, specialized domains that regulate access to DNA, and post-translational modifications, underlie the diverse functions that histones have acquired in evolution. | 20197778 | 2010-08-01 |
| 7364738 | Integrin inactivators: balancing cellular functions in vitro and in vivo. | Bouvard D, etal., Nat Rev Mol Cell Biol. 2013 Jul;14(7):430-42. doi: 10.1038/nrm3599. Epub 2013 May 30. | Integrins mediate cell-matrix and cell-cell interactions and integrate extracellular cues to the cytoskeleton and cellular signalling pathways. Integrin function on the cell surface is regulated by their activity switching such that intracellular proteins interacting with the integrin cytoplasmic do mains increase or decrease integrin-ligand binding affinity. It is widely accepted that integrin activation by specific proteins is essential for cell adhesion and integrin linkage to the actin cytoskeleton. However, there is also increasing evidence that integrin-inactivating proteins are crucial for appropriate integrin function in vitro and in vivo and that the regulation of integrin-ligand interactions is a fine-tuned balancing act between inactivation and activation. | 23719537 | 2013-09-01 |
| 7204696 | Mitochondria as sensors and regulators of calcium signalling. | Rizzuto R, etal., Nat Rev Mol Cell Biol. 2012 Sep;13(9):566-78. doi: 10.1038/nrm3412. Epub 2012 Aug 1. | During the past two decades calcium (Ca(2+)) accumulation in energized mitochondria has emerged as a biological process of utmost physiological relevance. Mitochondrial Ca(2+) uptake was shown to control intracellular Ca(2+) signalling, cell metabolism, cell survival and other cell-type specific fu nctions by buffering cytosolic Ca(2+) levels and regulating mitochondrial effectors. Recently, the identity of mitochondrial Ca(2+) transporters has been revealed, opening new perspectives for investigation and molecular intervention. | 22850819 | 2012-12-01 |
| 7775016 | Molecular control of the NEMO family of ubiquitin-binding proteins. | Clark K, etal., Nat Rev Mol Cell Biol. 2013 Oct;14(10):673-85. doi: 10.1038/nrm3644. Epub 2013 Aug 29. | Research over the past decade has revealed how NF-kappaB essential modulator (NEMO; also known as IKKgamma) regulates the IKKalpha-IKKbeta signalling axis in the innate immune system. The discovery that NEMO is a polyubiquitin-binding protein and that the IKK complex is modulated by other protein k inases that are themselves controlled by polyubiquitin chains has provided a deeper molecular understanding of the non-degradative roles of ubiquitylation. New mechanistic insights of NEMO and related polyubiquitin-binding proteins have become a paradigm for how the interplay between phosphorylation and ubiquitylation controls cell signalling networks in health and disease. | 23989959 | 2013-12-01 |
| 8661242 | Push back to respond better: regulatory inhibition of the DNA double-strand break response. | Panier S and Durocher D, Nat Rev Mol Cell Biol. 2013 Oct;14(10):661-72. doi: 10.1038/nrm3659. Epub 2013 Sep 4. | Single DNA lesions such as DNA double-strand breaks (DSBs) can cause cell death or trigger genome rearrangements that have oncogenic potential, and so the pathways that mend and signal DNA damage must be highly sensitive but, at the same time, selective and reversible. When initiated, boundaries mus t be set to restrict the DSB response to the site of the lesion. The integration of positive and, crucially, negative control points involving post-translational modifications such as phosphorylation, ubiquitylation and acetylation is key for building fast, effective responses to DNA damage and for mitigating the impact of DNA lesions on genome integrity. | 24002223 | 2013-06-01 |
| 9850108 | Regulation of microRNA biogenesis. | Ha M and Kim VN, Nat Rev Mol Cell Biol. 2014 Aug;15(8):509-24. doi: 10.1038/nrm3838. Epub 2014 Jul 16. | MicroRNAs (miRNAs) are small non-coding RNAs that function as guide molecules in RNA silencing. Targeting most protein-coding transcripts, miRNAs are involved in nearly all developmental and pathological processes in animals. The biogenesis of miRNAs is under tight temporal and spatial control, an d their dysregulation is associated with many human diseases, particularly cancer. In animals, miRNAs are approximately 22 nucleotides in length, and they are produced by two RNase III proteins--Drosha and Dicer. miRNA biogenesis is regulated at multiple levels, including at the level of miRNA transcription; its processing by Drosha and Dicer in the nucleus and cytoplasm, respectively; its modification by RNA editing, RNA methylation, uridylation and adenylation; Argonaute loading; and RNA decay. Non-canonical pathways for miRNA biogenesis, including those that are independent of Drosha or Dicer, are also emerging. | 25027649 | 2014-03-01 |
| 7349373 | Talins and kindlins: partners in integrin-mediated adhesion. | Calderwood DA, etal., Nat Rev Mol Cell Biol. 2013 Aug;14(8):503-17. doi: 10.1038/nrm3624. Epub 2013 Jul 17. | Integrin receptors provide a dynamic, tightly-regulated link between the extracellular matrix (or cellular counter-receptors) and intracellular cytoskeletal and signalling networks, enabling cells to sense and respond to their chemical and physical environment. Talins and kindlins, two families of F ERM-domain proteins, bind the cytoplasmic tail of integrins, recruit cytoskeletal and signalling proteins involved in mechanotransduction and synergize to activate integrin binding to extracellular ligands. New data reveal the domain structure of full-length talin, provide insights into talin-mediated integrin activation and show that RIAM recruits talin to the plasma membrane, whereas vinculin stabilizes talin in cell-matrix junctions. How kindlins act is less well-defined, but disease-causing mutations show that kindlins are also essential for integrin activation, adhesion, cell spreading and signalling. | 23860236 | 2013-09-01 |
| 8661249 | The ATM protein kinase: regulating the cellular response to genotoxic stress, and more. | Shiloh Y and Ziv Y, Nat Rev Mol Cell Biol. 2013 Apr;14(4):197-210. doi: 10.1038/nrm3546. Epub 2013 Mar 13. | The protein kinase ataxia-telangiectasia mutated (ATM) is best known for its role as an apical activator of the DNA damage response in the face of DNA double-strand breaks (DSBs). Following induction of DSBs, ATM mobilizes one of the most extensive signalling networks that responds to specific stimu li and modifies directly or indirectly a broad range of targets. Although most ATM research has focused on this function, evidence suggests that ATM-mediated phosphorylation has a role in the response to other types of genotoxic stress. Moreover, it has become apparent that ATM is active in other cell signalling pathways involved in maintaining cellular homeostasis. | 23486281 | 2013-06-01 |
| 7247276 | The mechanisms of Hedgehog signalling and its roles in development and disease. | Briscoe J and Therond PP, Nat Rev Mol Cell Biol. 2013 Jul;14(7):418-31. doi: 10.1038/nrm3598. Epub 2013 May 30. | The cloning of the founding member of the Hedgehog (HH) family of secreted proteins two decades ago inaugurated a field that has diversified to encompass embryonic development, stem cell biology and tissue homeostasis. Interest in HH signalling increased when the pathway was implicated in several ca ncers and congenital syndromes. The mechanism of HH signalling is complex and remains incompletely understood. Nevertheless, studies have revealed novel biological insights into this system, including the function of HH lipidation in the secretion and transport of this ligand and details of the signal transduction pathway, which involves Patched 1, Smoothened and GLI proteins (Cubitus interruptus in Drosophila melanogaster), as well as, in vertebrates, primary cilia. | 23719536 | 2013-06-01 |
| 9684930 | Unravelling the means to an end: RNA polymerase II transcription termination. | Kuehner JN, etal., Nat Rev Mol Cell Biol. 2011 May;12(5):283-94. doi: 10.1038/nrm3098. Epub 2011 Apr 13. | The pervasiveness of RNA synthesis in eukaryotes is largely the result of RNA polymerase II (Pol II)-mediated transcription, and termination of its activity is necessary to partition the genome and maintain the proper expression of neighbouring genes. Despite its ever-increasing biological significa nce, transcription termination remains one of the least understood processes in gene expression. However, recent mechanistic studies have revealed a striking convergence among several overlapping models of termination, including the poly(A)- and Sen1-dependent pathways, as well as new insights into the specificity of Pol II termination among its diverse gene targets. Broader knowledge of the role of Pol II carboxy-terminal domain phosphorylation in promoting alternative mechanisms of termination has also been gained. | 21487437 | 2011-12-01 |
