Effects of pathological mutations on the stability of a conserved amino acid triad in retinoschisin

Fraternali, Franca; Cavallo, Luigi; Musco, Giovanna

doi:10.1016/s0014-5793(03)00433-2

Cited by 31 publications

(30 citation statements)

References 33 publications

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“…3) (30, 31). The importance of W163 has been noted before in that it forms part of stacked "sandwich" with residues R200 and W122, likely stabilizing the long loop (158-172), coupling it to the core of the DS domain (20). The opposing side of the interface similarly includes several residues with XLRS-associated mutations: E72K, S73P, G74V, L103F, N104K, T185K, and E215V (Fig.…”

Section: F-mmentioning

confidence: 69%

“…The 16 subunit densities in the map are unambiguously recognizable as having the DS fold. The RS1 DS domain has been modeled several times with confidence based on the high conservation of the fold (18)(19)(20). We used this approach in conjunction with the cryo-EM map, starting from a computationally derived model in the SWISS-MODEL repository (swissmodel.expasy.org) (24).…”

Section: F-mmentioning

confidence: 99%

“…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)]. A similar mechanism for the interaction of RS1 with a membrane was proposed (20). However, the double-ring structure of RS1 does not fit this interpretation.…”

Section: F-mmentioning

confidence: 99%

“…Little progress has been made toward understanding the molecular mechanisms underlying the disease because of difficulty in producing the protein in sufficient quantities (5). In the absence of experimentally derived information, homology models of the RS1 monomer have been formulated based on existing X-ray structures of other DS domains (17)(18)(19)(20)(21). However, the arrangement of subunits in the putative octamer remained an open question.…”

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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: 69%

Section: F-mmentioning

confidence: 99%

Section: F-mmentioning

confidence: 99%

mentioning

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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“…The structure of mature RS1 contains 10 cysteines in positions 38,40,42,59,63,83,110,142,219, and 223, which are shared in an even proportion between Rs1 and discoidin domains ( Figure 4A). The structure of the discoidin domain and the positions of 5 cysteines were reported in several cases (Fraternali et al, 2003;Wang et al, 2006;Wu and Molday, 2003). The other 5 cysteines are located in the Rs1 domain of mature retinoschisin.…”

Section: Discoidin Domains and Molecular Modeling Of Rs1 Protein Strumentioning

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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Disease Mechanisms and Gene Therapy in A Mouse Model for X-Linked Retinoschisis

Molday

Min

Seeliger

et al.

Retinal Degenerative Diseases

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Effects of pathological mutations on the stability of a conserved amino acid triad in retinoschisin

Cited by 31 publications

References 33 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)

Disease Mechanisms and Gene Therapy in A Mouse Model for X-Linked Retinoschisis

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