The dynamin-like GTPase Sey1p mediates homotypic ER fusion in <i>S. cerevisiae</i>

Anwar, Kamran; Klemm, Robin W.; Condon, Amanda; Severin, Katharina; Zhang, Miaoxing; Ghirlando, Rodolfo; Hu, Junjie; Rapoport, Tom A.; Prinz, William A.

doi:10.1083/jcb.201111115

Cited by 103 publications

(172 citation statements)

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“…Nonbranched ER tubules are also observed on expression of dominant-negative ATL mutants (8,12). In addition, the fusion of ER vesicles in Xenopus laevis egg extracts is prevented by ATL antibodies or a cytosolic fragment of ATL (8,15), and the fusion of the ER in mating yeast cells is delayed on SEY1 deletion (16). Most convincingly, proteoliposomes containing purified ATL, Sey1p, or RHD3 undergo GTP-dependent fusion in vitro (9,13,16,17).…”

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confidence: 67%

“…In addition, the fusion of ER vesicles in Xenopus laevis egg extracts is prevented by ATL antibodies or a cytosolic fragment of ATL (8,15), and the fusion of the ER in mating yeast cells is delayed on SEY1 deletion (16). Most convincingly, proteoliposomes containing purified ATL, Sey1p, or RHD3 undergo GTP-dependent fusion in vitro (9,13,16,17). Defects in ATL-mediated ER fusion can cause hereditary spastic paraplegia, a neurodegenerative disease characterized by the shortening of the axons in corticospinal motor neurons, leading to progressive spasticity and weakness of the lower limbs (13,18).…”

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confidence: 99%

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Cis and trans interactions between atlastin molecules during membrane fusion

Liu

Bian

Romano

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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115

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Atlastin (ATL), a membrane-anchored GTPase that mediates homotypic fusion of endoplasmic reticulum (ER) membranes, is required for formation of the tubular network of the peripheral ER. How exactly ATL mediates membrane fusion is only poorly understood. Here we show that fusion is preceded by the transient tethering of ATL-containing vesicles caused by the dimerization of ATL molecules in opposing membranes. Tethering requires GTP hydrolysis, not just GTP binding, because the two ATL molecules are pulled together most strongly in the transition state of GTP hydrolysis. Most tethering events are futile, so that multiple rounds of GTP hydrolysis are required for successful fusion. Supported lipid bilayer experiments show that ATL molecules sitting on the same (cis) membrane can also undergo nucleotide-dependent dimerization. These results suggest that GTP hydrolysis is required to dissociate cis dimers, generating a pool of ATL monomers that can dimerize with molecules on a different (trans) membrane. In addition, tethering and fusion require the cooperation of multiple ATL molecules in each membrane. We propose a comprehensive model for ATL-mediated fusion that takes into account futile tethering and competition between cis and trans interactions. T he endoplasmic reticulum (ER) consists of tubules and sheets connected into a characteristic network by membrane fusion (1-3). In contrast to heterotypic fusion between viral and cellular membranes or between intracellular transport vesicles and target membranes, the fusing ER membranes are identical (i.e., homotypic fusion). The mechanism of heterotypic fusion has been studied extensively, leading to the concept that a conformational change of a viral fusion protein or the assembly of SNARE proteins pulls two opposing membranes together so that they can fuse (4-7). Recently, some insight has been obtained into homotypic ER fusion as well. This process is mediated by the atlastins (ATLs) in metazoans and by Sey1p/ROOT HAIR DEFECTIVE3 (RHD3)-related proteins in yeast and plants (8,9).The ATLs and Sey1p/RHD3 are membrane-bound GTPases that belong to the dynamin family (reviewed in refs. 10, 11). They contain cytosolic N-terminal GTPase (G) and helical bundle domains, followed by two closely spaced transmembrane (TM) segments and a cytosolic C-terminal tail (12)(13)(14). A role for the GTPases in ER fusion is suggested by the observation that their depletion or mutational inactivation leads to long, nonbranched tubules or fragmented ER (8, 9). Nonbranched ER tubules are also observed on expression of dominant-negative ATL mutants (8,12). In addition, the fusion of ER vesicles in Xenopus laevis egg extracts is prevented by ATL antibodies or a cytosolic fragment of ATL (8,15), and the fusion of the ER in mating yeast cells is delayed on SEY1 deletion (16). Most convincingly, proteoliposomes containing purified ATL, Sey1p, or RHD3 undergo GTP-dependent fusion in vitro (9,13,16,17). Defects in ATL-mediated ER fusion can cause hereditary spastic paraplegia, a neurodegenerativ...

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confidence: 67%

mentioning

confidence: 99%

Cis and trans interactions between atlastin molecules during membrane fusion

Liu

Bian

Romano

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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115

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“…Cells missing Sey1p and either Rtn1p or Yop1p have a reduced number of ER tubules, although cells missing only Rtn1p or Yop1p do not, indicating that Sey1p plays a role in maintaining ER tubules . Like atlastins, Sey1p also mediates homotypic ER fusion (Anwar et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

ER-shaping proteins facilitate lipid exchange between the ER and mitochondria in S. cerevisiae

Voss

Lahiri

Young

et al. 2012

Journal of Cell Science

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107

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SummaryThe endoplasmic reticulum (ER) forms a network of sheets and tubules that extends throughout the cell. Proteins required to maintain this complex structure include the reticulons, reticulon-like proteins, and dynamin-like GTPases called atlastins in mammals and Sey1p in Saccharomyces cerevisiae. Yeast cells missing these proteins have abnormal ER structure, particularly defects in the formation of ER tubules, but grow about as well as wild-type cells. We screened for mutations that cause cells that have defects in maintaining ER tubules to grow poorly. Among the genes we found were members of the ER mitochondria encounter structure (ERMES) complex that tethers the ER and mitochondria. Close contacts between the ER and mitochondria are thought to be sites where lipids are moved from the ER to mitochondria, a process that is required for mitochondrial membrane biogenesis. We show that ER to mitochondria phospholipid transfer slows significantly in cells missing both ER-shaping proteins and the ERMES complex. These cells also have altered steady-state levels of phospholipids. We found that the defect in ER to mitochondria phospholipid transfer in a strain missing ER-shaping proteins and a component of the ERMES complex was corrected by expression of a protein that artificially tethers the ER and mitochondria. Our findings indicate that ER-shaping proteins play a role in maintaining functional contacts between the ER and mitochondria and suggest that the shape of the ER at ER-mitochondria contact sites affects lipid exchange between these organelles.

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“…Previous studies illustrate that the addition of recombinant Rab GDI reduces the efficiency of ER network formation in vitro, presumably by disrupting the membrane association of all Rab proteins (Turner et al 1997;Audhya et al 2007). Notably, no Rab protein has been identified that localizes specifically to the ER and affects ER fusion, morphology or dynamics; however, a Rab-interacting SNARE protein, yeast Ufe1, has previously been implicated in ER assembly and provides more evidence for the involvement of a Rab GTPase in ER assembly (Patel et al 1998;Anwar et al 2012). …”

Section: Er Dynamics and Assemblymentioning

confidence: 99%

“…The factors that regulate homotypic ER membrane fusion must also be ER-specific, this is important because the ER is closely apposed and potentially tethered to nearly every membranebound compartment in the cell. Homotypic ER fusion is regulated by the Atlastin family of dynamin-like GTPases (Rismanchi et al 2008;Hu et al 2009;Orso et al 2009;Anwar et al 2012). Atlastin family members localize to the tubular ER and accumulate in a striking pattern at three-way junctions (Fig.…”

Section: Er Dynamics and Assemblymentioning

confidence: 99%

Endoplasmic Reticulum Structure and Interconnections with Other Organelles

English

Voeltz

2013

Cold Spring Harbor Perspectives in Biology

294

220

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The endoplasmic reticulum (ER) is a large, continuous membrane-bound organelle comprised of functionally and structurally distinct domains including the nuclear envelope, peripheral tubular ER, peripheral cisternae, and numerous membrane contact sites at the plasma membrane, mitochondria, Golgi, endosomes, and peroxisomes. These domains are required for multiple cellular processes, including synthesis of proteins and lipids, calcium level regulation, and exchange of macromolecules with various organelles at ER-membrane contact sites. The ER maintains its unique overall structure regardless of dynamics or transfer at ER-organelle contacts. In this review, we describe the numerous factors that contribute to the structure of the ER.T he endoplasmic reticulum (ER) is a dynamic organelle responsible for many cellular functions, including the synthesis of proteins and lipids, and regulation of intracellular calcium levels. This review focuses on the distinct and complex morphology of the ER. The structure of the ER is complex because of the numerous distinct domains that exist within one continuous membrane bilayer. These domains are shaped by interactions with the cytoskeleton, by proteins that stabilize membrane shape, and by a homotypic fusion machinery that allows the ER membrane to maintain its continuity and identity. The ER also contains domains that contact the plasma membrane (PM) and other organelles including the Golgi, endosomes, mitochondria, lipid droplets, and peroxisomes. ER contact sites with other organelles and the PM are both abundant and dispersed throughout the cytoplasm, suggesting that they too could influence the overall architecture of the ER. As we will discuss here, ER shape and distribution are regulated by many intrinsic and extrinsic forces. ER STRUCTURE AND FORMATION Domains of the ER Are Stabilized by Membrane-Shaping ProteinsThe endoplasmic reticulum (ER) is a large membrane-bound compartment spread throughout the cytoplasm of eukaryotic cells. It is divided into three major morphologies that include the nuclear envelope (NE), peripheral ER cisternae, and an interconnected tubular network

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The dynamin-like GTPase Sey1p mediates homotypic ER fusion in S. cerevisiae

Abstract: Budding yeast Sey1p functions analogously to mammalian atlastins in mediating ER fusion through a mechanism that is redundant with a second, ER SNARE-mediated fusion mechanism.

Cited by 103 publications

References 27 publications

Cis and trans interactions between atlastin molecules during membrane fusion

Cis and trans interactions between atlastin molecules during membrane fusion

ER-shaping proteins facilitate lipid exchange between the ER and mitochondria in S. cerevisiae

Endoplasmic Reticulum Structure and Interconnections with Other Organelles

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