doi: 10.1038/nrm3030pmid: 21119700
Super-resolution light microscopy reveals ultrastructural architecture of focal adhesions.
doi: 10.1038/nrm3033pmid: 21139637
Ubiquitin ligases for distinct proteolytic pathways cooperate to enhance substrate ubiquitylation.
Youle, Richard J.; Narendra, Derek P.
doi: 10.1038/nrm3028pmid: 21179058
Mitophagy is the selective elimination of mitochondria through autophagy. Recent studies have uncovered the molecular mechanisms mediating mitophagy in yeast and mammalian cells and have revealed that the dysregulation of one of these mechanisms — the PINK1–parkin-mediated signalling pathway — may contribute to Parkinson's disease.
Mick, David U.; Fox, Thomas D.; Rehling, Peter
doi: 10.1038/nrm3029pmid: 21179059
Respiratory chain subunits are made up of proteins encoded by nuclear and mitochondrial DNA, which assemble to form functional enzymes. New findings reveal that the mitochondrial translation of Cox1, the core component of cytochromecoxidase, is directly coupled to the assembly of this respiratory complex.
Zoncu, Roberto; Efeyan, Alejo; Sabatini, David M.
doi: 10.1038/nrm3025pmid: 21157483
The mammalian target of rapamycin (mTOR) is a highly conserved kinase that belongs to the phosphoinositide 3-kinase-related protein kinases (PIKK) family. mTOR participates in two distinct complexes, mTOR complex 1 (mTORC1) and mTORC2. mTORC1 integrates energy, nutrients, stress and growth factors and, in response to these stimuli, it drives the growth of cells, organs and whole organisms. mTORC2, which is activated by growth factors, promotes cell proliferation and survival. mTOR signalling maximizes energy storage and consumption. Upon chronic activation, mTORC1 drives insulin resistance by suppressing insulin receptor signalling and promoting fat accumulation. mTORC1 and mTORC2 are tightly linked with signalling pathways that lead to cancer. mTORC1 drives tumorigenesis by boosting translation of oncogenes, promoting anabolism and angiogenesis and suppressing autophagy. mTORC2 activates Akt and other AGC family kinases that promote cell proliferation and survival. Therapeutic strategies that are based on novel catalytic mTOR inhibitors have shown promising preclinical results. Our increasing knowledge of the molecular mechanisms underlying ageing is revealing a major role for mTOR in this process. Thus, understanding mTORC1 and mTORC2 biology is crucial for the development of novel drugs that can stave off ageing and age-related diseases.
Gaspar-Maia, Alexandre; Alajem, Adi; Meshorer, Eran; Ramalho-Santos, Miguel
doi: 10.1038/nrm3036pmid: 21179060
Pluripotent stem cells, such as embryonic stem cells, maintain the capacity to differentiate into all cell types of the body through a complex regulatory mechanism that involves a particular chromatin landscape. Pluripotent stem cells have been shown, by a variety of approaches, to have an open chromatin state with reduced levels of heterochromatin, both in vitro and in vivo. This open chromatin state is thought to be important for the maintenance of pluripotency. Open chromatin may be regulated by several chromatin regulators that are abundant in embryonic stem cells. These factors seem to actively prevent heterochromatin from expanding in the undifferentiated state. In the context of a globally open chromatin, other chromatin regulators contribute locally to the silencing of lineage-specific genes until differentiation is triggered, keeping pluripotent stem cells in a poised undifferentiated state. Reprogramming of somatic cells to pluripotent stem cells requires re-opening of chromatin in a process that probably involves some of the same factors that maintain open chromatin. Chromatin re-opening during reprogramming may not always be complete and thus leaves an epigenetic memory of the original cell type. The overcoming of epigenetic barriers during somatic cell reprogramming to pluripotency appears to have molecular parallels with cellular transformation in cancer.
Schleiff, Enrico; Becker, Thomas
doi: 10.1038/nrm3027pmid: 21139638
The vast majority of mitochondrial and chloroplast proteins are cytosolically synthesized and have to be translocated into the organelle. Precursor proteins contain amino acid-based signals. These signals supply information allowing the proteins to target, and interact with, the cytosolic chaperones that provide guidance to organelles. Translocases at the outer membrane of mitochondria and chloroplasts form the general entry gate into both organelles. The translocases of both organelles consist of three receptors, which bind to the multitude of different precursor proteins and deliver them to a translocation pore formed by a protein with β-barrel structure. Despite similarities with respect to their composition, the translocons differ with respect to signal length requirement and their energizing of the translocation event. The mode of translocation is also distinct between the translocation machineries: mitochondrial import across the outer membrane is affinity-driven, whereas the passage of precursor proteins into chloroplasts is modulated by GTP binding and hydrolysis, and by phosphorylation events.
Morth, J. Preben; Pedersen, Bjørn P.; Buch-Pedersen, Morten J.; Andersen, Jens Peter; Vilsen, Bente; Palmgren, Michael G.; Nissen, Poul
doi: 10.1038/nrm3031pmid: 21179061
Ions are transported across the plasma membrane by molecular pumps to generate chemical gradients and regulate pH or cell growth. P-type ATPases are a family of molecular pumps that transport cations in or outside the cell. Members of this family include the Na+,K+-ATPase (found in animals) and the H+-ATPase (found in plants and fungi). The Na+,K+-ATPase exchanges Na+ for K+ and the H+-ATPase pumps H+ out of the cell. P-type ATPases undergo conformational changes as part of their functional cycle, giving rise to two enzymatic states, E1 and E2, with different affinities for the primary transported ions. P-type ATPases contain a cytoplasmic core comprising the phosphorylation, nucleotide-binding and actuator domains. These carry out autophosphatase activities and are responsible for ATP hydrolysis. All P-type ATPases have six transmembrane helices (M1–M6). The Na+,K+-ATPase and the H+-ATPase have additional transmembrane helices (M7–M10) that may provide specificity or stability in the Na+,K+-ATPase and the H+-ATPase, respectively. Many P-type ATPases also have regulatory domains that fine-tune their activity in ion pumping. Crystal structures and functional studies of the Na+,K+-ATPase and the H+-ATPase have provided insight into their mechanisms of action in eukaryotic cells.
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