Retinoschisin Is a Peripheral Membrane Protein with Affinity for Anionic Phospholipids and Affected by Divalent Cations

Vijayasarathy, Camasamudram; Takada, Yuji; Zeng, Yong; Bush, Ronald A.; Sieving, Paul A.

doi:10.1167/iovs.06-0915

Cited by 53 publications

(60 citation statements)

References 29 publications

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“…The connections between cells can be very complex, as manifested in the many proteins involved in tight junctions (2). Similarly, RS1 does not function in isolation, with other possible participants being charged lipids (33) and glycoproteins (36,38,39). In our scheme, the protruding loops (spikes) then interact laterally with these other actors, forming a densely packed assembly of proteins sandwiched between the membranes from opposing photoreceptor or bipolar cells.…”

Section: F-mmentioning

confidence: 98%

“…S5). The most prominent loop has at its tip residues 87-93 (corresponding to spike 1), including the bulky Y89 and W92 associated with XLRS and implicated in binding to phospholipids (33). Several DS domain proteins bind to membranes, and in several cases it was proposed that hydrophobic residues in the spikes embed in the membrane [C2 domains of factor V (32), factor VIII (34), and lactadherin (35)].…”

Section: F-mmentioning

confidence: 99%

“…Immunoelectron microscopy located an abundance of RS1 between closely packed photoreceptor inner segments, where the separation between membranes is on the order of 100-200 Å (33). The connections between cells can be very complex, as manifested in the many proteins involved in tight junctions (2).…”

Section: F-mmentioning

confidence: 99%

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Paired octamer rings of retinoschisin suggest a junctional model for cell–cell adhesion in the retina

Tolun

Vijayasarathy

Huang

et al. 2016

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

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Retinoschisin (RS1) is involved in cell-cell junctions in the retina, but is unique among known cell-adhesion proteins in that it is a soluble secreted protein. Loss-of-function mutations in RS1 lead to early vision impairment in young males, called X-linked retinoschisis. The disease is characterized by separation of inner retinal layers and disruption of synaptic signaling. Using cryo-electron microscopy, we report the structure at 4.1 Å, revealing double octamer rings not observed before. Each subunit is composed of a discoidin domain and a small N-terminal (RS1) domain. The RS1 domains occupy the centers of the rings, but are not required for ring formation and are less clearly defined, suggesting mobility. We determined the structure of the discoidin rings, consistent with known intramolecular and intermolecular disulfides. The interfaces internal to and between rings feature residues implicated in X-linked retinoschisis, indicating the importance of correct assembly. Based on this structure, we propose that RS1 couples neighboring membranes together through octamer-octamer contacts, perhaps modulated by interactions with other membrane components.retinoschisin | X-linked retinoschisis | discoidin domain | cryo-electron microscopy | single particle analysis T he structural integrity and functioning of tissues are highly dependent on cell-cell junctions. These are typically composed of two similar opposing layers of interacting proteins embedded as oligomers or arrays in the cellular membranes. For example, paired arrays of cadherins are found in adherens junctions and desmosomes (1); of claudins and occludins in tight junctions (2, 3); and of connexin channels in gap junctions (4). The back-to-back architecture of these junctions is fundamental to their adhesive function.The retina features another protein implicated in cell-cell adhesion, retinoschisin (RS1). RS1 is a 24-kDa protein expressed exclusively by photoreceptors and bipolar cells in the retina (5) and pineal gland (6). Loss-of-function mutants of RS1 lead to progressive visual impairment in a disease called X-linked retinoschisis (XLRS) (7-9). The clinical manifestation is a pathological separation of retinal layers, leading to structural splitting and cavity (or "schisis") formation (10). Additionally, the bipolar cells show disorganization (11) and failure to maintain synaptic organization (9). Both XLRS patients and RS1 gene knockout mouse models (Rs1-KO) show similar phenotypes: schisis/splitting through retinal layers and synaptic transmission defects manifested as reduced b-wave amplitudes on the clinical electroretinogram ( Fig. S1) (8, 12). RS1 gene therapy rescues the XLRS mouse phenotype (9, 13) and human RS1 gene therapy trials are underway (ClinicalTrials.gov: NCT02317887; NCT02416622).RS1 is secreted as a soluble disulfide bond-stabilized octamer (14, 15). Most of the monomer comprises a discoidin (DS) domain, a globular fold that is highly conserved over many proteins with diverse functions (16). Little progress has been made toward...

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Section: F-mmentioning

confidence: 98%

Section: F-mmentioning

confidence: 99%

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Paired octamer rings of retinoschisin suggest a junctional model for cell–cell adhesion in the retina

Tolun

Vijayasarathy

Huang

et al. 2016

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

Self Cite

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“…This implies primary involvement of the inner retina where schisis cavities occur in XLRS. The identification of Ltype voltage-gated calcium channels (Shi et al, 2009), Na/K ATPase (alpha3, beta2 isoforms) (Friedrich et al), the sterile alpha and TIR motif-containing protein SARM1 (Molday, 2007), and phospholipids/Ca 2+ (Vijayasarathy et al, 2007) as potential RS1 interacting ligands corroborate a role for RS1 in cell signaling events as well. However, ERG show considerable variation in this disease and ophthalmologists have to be aware about the possibility of relative ERG b-wave preservation especially in presence of atypical or mild manifestation of the disease (Eksandh et al, 2005;Sieving et al, 1999a;Vijayasarathy et al, 2009).…”

Section: Photoreceptor and Bipolar Cell Function As Seen In The Full mentioning

confidence: 82%

“…It encodes a conserved discoidin domain homologous to proteins involved in cell adhesion and cell-cell interactions. Based on its structural features, RS1 is believed to hold retinal cells together, to preserve the retinal architecture, and to function as an adhesive protein for the structural and functional integrity of the retina Vijayasarathy et al, 2007). It may mediate the association of the extracellular matrix with the surface of photoreceptors and other retinal cells to promote cell adhesion and thereby stabilize the cellular architecture of the highly structured retinal tissues.…”

mentioning

confidence: 99%

Molecular Modeling of Protein Structure, Biology of Disease and Clinical Electroretinography in Human X-Linked Retinoschisis (XLRS)

Sergeev¹,

Bowles²,

Ziccardi³

et al. 2011

Electroretinograms

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A number of mutations in RS1 co-segregate with XLRS providing strong evidence that the disease is caused by mutations in the RS1 gene (Sauer et al., 1997). Although inherited mutations in the RS1 gene have been shown to cause an XLRS phenotype, the functional impact of most missense variants that result in a single amino acid change is less well defined. RS1 is a 24-kDa secreted protein which is expressed exclusively in the retina (Reid et al., 1999), pineal gland (Takada et al., 2006, and uterus (Huopaniemi et al., 1999). In retinal layers it is found in photoreceptor cells and in neurons of the inner retina (Figure 1). It encodes a conserved discoidin domain homologous to proteins involved in cell adhesion and cell-cell interactions. Based on its structural features, RS1 is believed to hold retinal cells together, to preserve the retinal architecture, and to function as an adhesive protein for the structural and functional integrity of the retina Vijayasarathy et al., 2007). It may mediate the association of the extracellular matrix with the surface of photoreceptors and other retinal cells to promote cell adhesion and thereby stabilize the cellular architecture of the highly structured retinal tissues. There exist three primary mechanisms that may be responsible for the loss of function of the RS1 protein: the misfolding of the discoidin domain, which negatively influences the putative adhesive properties of the protein; the defective disulfide-linked subunit assembly of RS1 into dimers and octamers; or the inability of RS1 to insert into endoplasmic reticulum membrane as part of the protein secretion process. Retinal morphology in retinoschisis: photoreceptors disruption and altered photoreceptor/bipolar cells synapse in the RS1-KO mouseCurrently, there are three mouse models of human XLRS. One has been generated by homologus DNA insertion across the endogenous RS1 gene (Weber et al., 2002), presenting a phenotype consisting of abnormal retinal architecture with schisis in the inner nuclear layer, reduced outer segment layer thickness, loss of photoreceptors, and a selective ERG bwave reduction with relative sparing of the a-wave similar to XLRS male subjects. A second RS1 knock-out mouse model (Zeng et al., 2004) was created by substituting a neomycin resistance cassette for exon 1 and 1.6 kb in intron 1 of RS1h, the murine orthologue of the human RS1 gene. This model also displayed structural and functional features similar to those of human XLRS, including the electronegative ERG waveform and splitting in the inner nuclear layer similar to retinoschisis cavities by 6 months of age. They also demonstrated displacement of cells from the photoreceptor outer nuclear layer (ONL) and reduced thickness of the outer segment layer (Zeng et al., 2004). More recently, a third mouse model was generated using an ENU mutagenesis approach (Jablonski et al., 2005) derived from an induced mutation in intron 2 of RS1h, which leads to two novel splice variants. It is remarkable that, similar to the human condition, male ho...

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Retinal Morphological Changes of Patients With X-linked Retinoschisis Evaluated by Fourier-Domain Optical Coherence Tomography

Gerth

Zawadzki²,

Werner³

et al. 2008

Arch Ophthalmol

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Retinoschisin Is a Peripheral Membrane Protein with Affinity for Anionic Phospholipids and Affected by Divalent Cations

Cited by 53 publications

References 29 publications

Paired octamer rings of retinoschisin suggest a junctional model for cell–cell adhesion in the retina

Paired octamer rings of retinoschisin suggest a junctional model for cell–cell adhesion in the retina

Molecular Modeling of Protein Structure, Biology of Disease and Clinical Electroretinography in Human X-Linked Retinoschisis (XLRS)

Retinal Morphological Changes of Patients With X-linked Retinoschisis Evaluated by Fourier-Domain Optical Coherence Tomography

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