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      A new family of StART domain proteins at membrane contact sites has a role in ER-PM sterol transport

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          Sterol traffic between the endoplasmic reticulum (ER) and plasma membrane (PM) is a fundamental cellular process that occurs by a poorly understood non-vesicular mechanism. We identified a novel, evolutionarily diverse family of ER membrane proteins with StART-like lipid transfer domains and studied them in yeast. StART-like domains from Ysp2p and its paralog Lam4p specifically bind sterols, and Ysp2p, Lam4p and their homologs Ysp1p and Sip3p target punctate ER-PM contact sites distinct from those occupied by known ER-PM tethers. The activity of Ysp2p, reflected in amphotericin-sensitivity assays, requires its second StART-like domain to be positioned so that it can reach across ER-PM contacts. Absence of Ysp2p, Ysp1p or Sip3p reduces the rate at which exogenously supplied sterols traffic from the PM to the ER. Our data suggest that these StART-like proteins act in trans to mediate a step in sterol exchange between the PM and ER.


          eLife digest

          Membranes are crucial structures for cells that are made primarily of fat molecules. The most important membrane is the external one that surrounds cells and keeps the outside world out and cellular contents in. The single most common fat component in the external membrane is cholesterol, which makes the membrane rigid and better able to withstand the outside world. So even though excess cholesterol contributes to diseases such as heart disease, stroke and Alzheimer's, the external membrane of every cell needs about a billion cholesterol molecules for its normal function. But how do cells manage the traffic of these molecules to their destination?

          It is known that when external membranes are short of cholesterol they make it at a different cellular location. There is an internal network—called the endoplasmic reticulum—that spreads just about everywhere throughout the cell. This network is where fats like cholesterol are made when the cell has not got enough, and where they are converted into an inert form when the cell has too much. What is not known is how cholesterol moves to and fro between this network and the external membrane.

          One theory is that cholesterol and other fats move only where the internal network comes into close contact with the external membrane, without quite touching. This theory comes in part from the finding that many of the proteins found in the narrow gaps between the internal network and the external membrane are capable of transferring fats across the gap. However, one of the missing supports for this theory is that no protein that transfers cholesterol across this gap has been found.

          Gatta, Wong, Sere et al. used computational tools to scan the database of known proteins for those that might be able to transfer cholesterol, and found a new family of fat transfer proteins. Further experiments showed that these proteins only bind to cholesterol out of all the fats. Next, Gatta, Wong, Sere et al. studied what the proteins do in cells, but instead of looking at the proteins in human cells they studied the related proteins in yeast. This is because the details of both the traffic of cholesterol and contacts between the internal network and the external membrane are in many respects understood better in yeast than in human cells.

          Gatta, Wong, Sere et al. found the cholesterol transfer proteins were embedded in regions where the internal network was in close contact with the external membrane. Also, in cells that lacked these proteins, cholesterol added to the external membrane had difficulty transferring to the internal network.

          These results together suggest that the newly identified lipid transfer proteins exchange lipids between the plasma membrane and endoplasmic reticulum at membrane contact sites. Further research is required to understand in detail how these proteins work.


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          Most cited references 71

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          The increase in the number of large data sets and the complexity of current probabilistic sequence evolution models necessitates fast and reliable phylogeny reconstruction methods. We describe a new approach, based on the maximum- likelihood principle, which clearly satisfies these requirements. The core of this method is a simple hill-climbing algorithm that adjusts tree topology and branch lengths simultaneously. This algorithm starts from an initial tree built by a fast distance-based method and modifies this tree to improve its likelihood at each iteration. Due to this simultaneous adjustment of the topology and branch lengths, only a few iterations are sufficient to reach an optimum. We used extensive and realistic computer simulations to show that the topological accuracy of this new method is at least as high as that of the existing maximum-likelihood programs and much higher than the performance of distance-based and parsimony approaches. The reduction of computing time is dramatic in comparison with other maximum-likelihood packages, while the likelihood maximization ability tends to be higher. For example, only 12 min were required on a standard personal computer to analyze a data set consisting of 500 rbcL sequences with 1,428 base pairs from plant plastids, thus reaching a speed of the same order as some popular distance-based and parsimony algorithms. This new method is implemented in the PHYML program, which is freely available on our web page:
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            The HHpred interactive server for protein homology detection and structure prediction

            HHpred is a fast server for remote protein homology detection and structure prediction and is the first to implement pairwise comparison of profile hidden Markov models (HMMs). It allows to search a wide choice of databases, such as the PDB, SCOP, Pfam, SMART, COGs and CDD. It accepts a single query sequence or a multiple alignment as input. Within only a few minutes it returns the search results in a user-friendly format similar to that of PSI-BLAST. Search options include local or global alignment and scoring secondary structure similarity. HHpred can produce pairwise query-template alignments, multiple alignments of the query with a set of templates selected from the search results, as well as 3D structural models that are calculated by the MODELLER software from these alignments. A detailed help facility is available. As a demonstration, we analyze the sequence of SpoVT, a transcriptional regulator from Bacillus subtilis. HHpred can be accessed at .
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              Mitofusin 2 tethers endoplasmic reticulum to mitochondria.

              Juxtaposition between endoplasmic reticulum (ER) and mitochondria is a common structural feature, providing the physical basis for intercommunication during Ca(2+) signalling; yet, the molecular mechanisms controlling this interaction are unknown. Here we show that mitofusin 2, a mitochondrial dynamin-related protein mutated in the inherited motor neuropathy Charcot-Marie-Tooth type IIa, is enriched at the ER-mitochondria interface. Ablation or silencing of mitofusin 2 in mouse embryonic fibroblasts and HeLa cells disrupts ER morphology and loosens ER-mitochondria interactions, thereby reducing the efficiency of mitochondrial Ca(2+) uptake in response to stimuli that generate inositol-1,4,5-trisphosphate. An in vitro assay as well as genetic and biochemical evidences support a model in which mitofusin 2 on the ER bridges the two organelles by engaging in homotypic and heterotypic complexes with mitofusin 1 or 2 on the surface of mitochondria. Thus, mitofusin 2 tethers ER to mitochondria, a juxtaposition required for efficient mitochondrial Ca(2+) uptake.

                Author and article information

                Role: Reviewing editor
                eLife Sciences Publications, Ltd
                22 May 2015
                : 4
                [1 ]deptDepartment of Cell Biology , UCL Institute of Ophthalmology , London, United Kingdom
                [2 ]deptDepartment of Biochemistry , Weill Cornell Medical College , New York, United States
                [3 ]deptDepartment of Neuroscience, Physiology and Pharmacology , University College London , London, United Kingdom
                Yale University , United States
                Yale University , United States
                Author notes
                [* ]For correspondence: tim.levine@

                These authors contributed equally to this work.

                © 2015, Gatta et al

                This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.

                Funded by: Qatar National Research Fund (QNRF);
                Award ID: NPRP 5-669-1-112
                Award Recipient :
                Funded by: FundRef, Medical Research Council (MRC);
                Award ID: MR/J006580/1
                Award Recipient :
                Funded by: FundRef, European Commission;
                Award ID: Sphingonet ITN, project ref 289278
                Award Recipient :
                The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
                Research Article
                Cell Biology
                Custom metadata
                A new family of sterol-specific lipid transfer proteins has been found that anchors in the endoplasmic reticulum; some of these proteins stretch across membrane contacts and mediate sterol traffic from the plasma membrane.


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