A Class of Membrane Proteins Shaping the Tubular Endoplasmic Reticulum

Voeltz, Gia K.; Prinz, William A.; Shibata, Yoko; Rist, Julia M.; Rapoport, Tom A.

doi:10.1016/j.cell.2005.11.047

Cited by 1,042 publications

(1,287 citation statements)

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“…They are classified into 2 subfamilies: (1) REEP1 to REEP4 and (2) REEP5 and REEP6. A direct role for REEP5/DP1 in shaping ER tubules has been established 11. Whether REEPs contribute to SR membrane shaping and the associated SR Ca 2+ handling and cardiac function remains to be characterized.…”

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confidence: 99%

REEP5 (Receptor Accessory Protein 5) Acts as a Sarcoplasmic Reticulum Membrane Sculptor to Modulate Cardiac Function

Yao

Xie

et al. 2018

JAHA

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BackgroundHeart failure is a complex syndrome characterized by cardiac contractile impairment with high mortality. Defective intracellular Ca2+ homeostasis is the central cause under this scenario and tightly links to ultrastructural rearrangements of sarcolemmal transverse tubules and the sarcoplasmic reticulum (SR); however, the modulators of the SR architecture remain unknown. The SR has been thought to be a specialized endoplasmic reticulum membrane system. Receptor accessory proteins (REEPs)/DP1/Yop1p are responsible for shaping high‐curvature endoplasmic reticulum tubules. This study aimed to determine the role of REEPs in SR membrane shaping and thus cardiac function.Methods and ResultsWe identified REEP5 (receptor accessory protein 5) as more highly expressed than other REEP members in adult rat ventricular myocardium, and it was downregulated in the failing hearts. Targeted inactivation of REEP5 in rats specially deformed the cardiac SR membrane without affecting transverse tubules, and this was visualized by focused ion beam scanning electron microscopy–based 3‐dimensional reconstruction. Accordingly, simultaneous recordings of depolarization‐induced Ca2+ currents and Ca2+ transients in REEP5‐null cardiomyocytes revealed normal L‐type Ca2+ channel currents but a depressed SR Ca2+ release. Consequently, the excitation–contraction coupling gain of cardiomyocytes and consequent cardiac contractility were compromised. REEP5 deficiency did not alter the expression of major proteins involved in Ca2+ handling in the heart.Conclusions REEP5 modulates cardiac function by shaping the SR. REEP5 defect deforms the SR architecture to depress cardiac contractility. REEP5‐dependent SR shaping might have potential as a therapeutic target for heart failure.

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confidence: 99%

REEP5 (Receptor Accessory Protein 5) Acts as a Sarcoplasmic Reticulum Membrane Sculptor to Modulate Cardiac Function

Yao

Xie

et al. 2018

JAHA

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“…Reticulon (RTN) 2 proteins are a group of membrane-bound proteins that are largely localized in the endoplasmic reticulum (ER) (1,2), perhaps more restricted to the tubular ER (3). RTNs exist in plants, fungi, and animals (4).…”

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The Membrane Topology of RTN3 and Its Effect on Binding of RTN3 to BACE1

Shi

et al. 2007

Journal of Biological Chemistry

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Reticulon 3 (RTN3) has recently been shown to modulate Alzheimer BACE1 activity and to play a role in the formation of dystrophic neurites present in Alzheimer brains. Despite the functional importance of this protein in Alzheimer disease pathogenesis, the functional correlation to the structural domain of RTN3 remained unclear. RTN3 has two long transmembrane domains, but its membrane topology was not known. We report here that the first transmembrane domain dictates membrane integration and its membrane topology. RTN3 adopts a -shape structure with two ends facing the cytosolic side. Subtle changes in RTN3 membrane topology can disrupt its binding to BACE1 and its inhibitory effects on BACE1 activity. Thus, the determination of RTN3 membrane topology may provide an important structural basis for our understanding of its cellular functions. Reticulon (RTN)2 proteins are a group of membrane-bound proteins that are largely localized in the endoplasmic reticulum (ER) (1, 2), perhaps more restricted to the tubular ER (3). RTNs exist in plants, fungi, and animals (4). In mammalian genomes, four independent reticulon genes, rtn1 to rtn4, have been identified to encode a large number of gene products (1, 2). All RTNs are composed of a variable length of N-terminal domain, which is completely divergent among RTN members, and a highly conserved RTN homology domain (RHD) that is unique to this family of proteins. Within the RHD, there exist two long stretches (28 -36 amino acids) of hydrophobic residues, and each is expected to embed RTNs in the membrane.The divergent N-terminal domain among RTNs potentially allows each RTN member to exert its specific function. RTN4, or its more popular acronym Nogo, is identified as a critical inhibitory molecule in axonal growth and regeneration (5, 6). Recently, reticulon proteins (including Nogo) have been shown to interact with ␤-secretase, also known as ␤-site APP-cleaving enzyme 1 (BACE1) (7-10), and this interaction negatively modulates the enzymatic activity of BACE1 (11-13). Among the RTNs, we have paid particular attention to RTN3 because of its strong inhibitory effects on BACE1 activity and high expression by neurons. RTN3 is localized not only in the ER compartment but also in the Golgi (11, 14), axons, dendrites, and growth cone (15). The localization of RTN3 in the neuritic region suggests its potential role in neuritic functions. Most recently, we have demonstrated that RTN3 also plays a role in the formation of dystrophic neurites in Alzheimer brains (15).Because of the important role of RTN3 in Alzheimer pathogenesis, we set out to study the structure and function of RTN3. We report herein that the first transmembrane stretch or domain (TM1) is important for the membrane insertion of RTN3. Disruption of the TM1 of RTN3 results in misfolding of the mutant protein and failure to integrate the protein into the membrane. We also show that RTN3 adopts a -shape membrane topology with both the N-and C-terminal ends facing the cytosolic side. Knowledge from this study will be...

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“…In yeast, Rtn1p (one of reticulons) and Yop1p are most abundant membrane proteins [7]. Yeast lacking both reticulons and Yop1p had disrupted ER under normal growth conditions [5]. Conversely, the overexpression of certain isoforms results in long, unbranched tubules.…”

Section: Introductionmentioning

confidence: 99%

“…The possible model is based on mechanisms that generate or stabilize high curvature in membranes. Two protein families, the reticulons (Rtns) and DP1/Yop1 (Yip one partner), have been shown to shape the membrane bilayer of ER tubules in multiple eukaryotes, including animals, plants, and yeast [5][6]. Members of both families are ubiquitously expressed in all eukaryotic cells.…”

Section: Introductionmentioning

confidence: 99%

Molecular Cloning and Structure Analysis Of MpYop1, a Membrane Protein in Monascus purpureus

Hao-ming¹,

Gao²

2015

Proceedings of the International Conference on Advances in Energy, Environment and Chemical Engineering

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Abstract. In all eukaryotes, the peripheral endoplasmic reticulum (ER) branches out of the nuclear envelope as a membrane network of interconnected tubules and membrane sheets with a single lumen. In yeast, Rtn1p and Yop1p are major, redundant components required to maintain the tubular ER under normal circumstances. In this work, we have investigated the homolog of the yeast Yop1 protein in Monascus purpureus. An M. purpureus cDNA library was constructed, and the MpYop1 cDNA was isolated from the cDNA library by random sequencing method. The cDNA was 1008 bp in length, contains a predicted 516 bp ORF that encodes 171 amino acids, the gene was designated MpYop1. The deduced amino acid sequence showed homology to Yop1 from fungi. The TM topology model of MpYop1 was built, the secondary structure is similar to yeast Yop1p. MpYop1 contains four transmembrane α-helices connected by a cytoplasmic loop and two extracellar loop, both the N and C termini are located in the cytoplasm side of ER membrane. According to functions of Yop1 in Yeast, we implicated that the MpYop1 would involved in stabilization of tubule ER. IntroductionThe endoplasmic reticulum (ER) is a continuous membrane system which has many different functions. These include the translocation of proteins across the ER membrane; the folding and modification of proteins in the ER lumen; the synthesis of phospholipids and steroids on the cytosolic side of the ER membrane; and the storage of calcium ions in the ER lumen and their regulated release into the cytosol [1][2]. ER is often tightly associated with almost every other membrane-bound compartment in the cell including the plasma membrane, nuclear envelope, mitochondria, golgi, vacuoles and peroxisomes. Interactions between these organelles have shown to be functionally important [3].The ER consists of the nuclear envelope and a peripheral network of tubules and membrane sheets. Peripheral ER sheets with little curvature except at their edges and the nuclear envelope with low curvature except where the nuclear pores are inserted. The ER is composed of a network of "rough," ribosome-studded sheets and smooth tubules that are continuous with the nuclear envelope. These subdomains are plastic and are remodeled in response to the needs of the cell. During interphase, enhanced protein synthesis and secretion promote morphology rich in sheets and rough ER, whereas lipid and steroid synthesis and detoxification promote abundant tubular smooth ER [4].The mechanism of ER network formation and maintenance is unclear. The possible model is based on mechanisms that generate or stabilize high curvature in membranes. Two protein families, the reticulons (Rtns) and DP1/Yop1 (Yip one partner), have been shown to shape the membrane bilayer of ER tubules in multiple eukaryotes, including animals, plants, and yeast [5][6]. Members of both families are ubiquitously expressed in all eukaryotic cells. In yeast, Rtn1p (one of reticulons) and Yop1p are most abundant membrane proteins [7]. Yeast lacking both reticulons and Yop1...

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A Class of Membrane Proteins Shaping the Tubular Endoplasmic Reticulum

Cited by 1,042 publications

References 36 publications

REEP5 (Receptor Accessory Protein 5) Acts as a Sarcoplasmic Reticulum Membrane Sculptor to Modulate Cardiac Function

REEP5 (Receptor Accessory Protein 5) Acts as a Sarcoplasmic Reticulum Membrane Sculptor to Modulate Cardiac Function

The Membrane Topology of RTN3 and Its Effect on Binding of RTN3 to BACE1

Molecular Cloning and Structure Analysis Of MpYop1, a Membrane Protein in Monascus purpureus

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