Predicted and Measured Disorder in Peripherin/rds, a Retinal Tetraspanin

Ritter, Linda M.; Arakawa, Tsutomu; Goldberg, Andrew F.X.

doi:10.2174/0929866054696217

Cited by 23 publications

(41 citation statements)

References 43 publications

(87 reference statements)

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“…(A) Domain structure of full-length P/rds. Transmembrane domains (TM) are shaded gray (Connell and Molday, 1990); intrinsically disordered regions are shaded pink (Ritter et al, 2005); extracellular 2 (EC2) domain mediates oligomerization (Loewen and Molday, 2000;Goldberg et al, 2001). (B) Sequence alignment of the C-termini of commonly studied P/rds orthologs.…”

Section: Resultsmentioning

confidence: 99%

“…Interestingly, other than the membrane-inducible AH, the ,7 kDa P/rds C-terminus is intrinsically disordered in aqueous solution (Ritter et al, 2005;Edrington et al, 2007). We have suggested previously that the plasticity present in this domain makes additional functional roles likely (Ritter et al, 2005), and several studies have found that subcellular targeting information is contained within this domain Salinas et al, 2013).…”

Section: Discussionmentioning

confidence: 98%

“…Because curvature induction by AHcontaining proteins is typically amplified by protein polymerization (Farsad and De Camilli, 2003;Campelo et al, 2008;Shibata et al, 2009), it is tempting to speculate that P/rds self-assembly might play a similar role. Although the P/rds Cterminus does not itself self-associate (Goldberg et al, 2001;Tam et al, 2004;Ritter et al, 2005), the P/rds intradiskal EC2 (extracellular 2) domain mediates several stages of functionally critical protein self-assembly (Goldberg and Molday, 1996a;Loewen and Molday, 2000;Goldberg et al, 2001;Kedzierski et al, 2001;Chakraborty et al, 2009). It is therefore possible that AH clustering and wedging (hydrophobic insertion) effects might be amplified by P/rds polymerization.…”

Section: Discussionmentioning

confidence: 99%

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Membrane curvature generation by a C-terminal amphipathic helix in peripherin-2/rds, a tetraspanin required for photoreceptor sensory cilium morphogenesis

Khattree

Ritter

Goldberg

2013

Journal of Cell Science

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SummaryVertebrate vision requires photon absorption by photoreceptor outer segments (OSs), structurally elaborate membranous organelles derived from non-motile sensory cilia. The structure and function of OSs depends on a precise stacking of hundreds of membranous disks. Each disk is fully (as in rods) or partially (as in cones) bounded by a rim, at which the membrane is distorted into an energetically unfavorable high-curvature bend; however, the mechanism(s) underlying disk rim structure is (are) not established. Here, we demonstrate that the intrinsically disordered cytoplasmic C-terminus of the photoreceptor tetraspanin peripherin-2/rds (P/rds) can directly generate membrane curvature. A P/rds C-terminal domain and a peptide mimetic of an amphipathic helix contained within it each generated curvature in liposomes with a composition similar to that of OS disks and in liposomes generated from native OS lipids. Association of the C-terminal domain with liposomes required conical phospholipids, and was promoted by membrane curvature and anionic surface charge, results suggesting that the P/rds C-terminal amphipathic helix can partition into the cytosolic membrane leaflet to generate curvature by a hydrophobic insertion (wedging) mechanism. This activity was evidenced in full-length P/rds by its induction of small-diameter tubulovesicular membrane foci in cultured cells. In sum, the findings suggest that curvature generation by the P/rds Cterminus contributes to the distinctive structure of OS disk rims, and provide insight into how inherited defects in P/rds can disrupt organelle structure to cause retinal disease. They also raise the possibility that tethered amphipathic helices can function for shaping cellular membranes more generally.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

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Membrane curvature generation by a C-terminal amphipathic helix in peripherin-2/rds, a tetraspanin required for photoreceptor sensory cilium morphogenesis

Khattree

Ritter

Goldberg

2013

Journal of Cell Science

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“…The PerCter is monomeric and adopts an extended or random-coil-like conformation in solution (4). The diversity of structural and functional characteristics exemplified by the PerCter within the cellular milieu in which p/rds resides are common features of the growing family of intrinsically disordered proteins (IDPs).…”

Section: Discussionmentioning

confidence: 99%

“…with NET-7, its closest TMF4 relative (3,4). These tetra-spanning proteins have a short cytoplasmic N-terminal region and a large hydrophilic extracellular loop (EC2) with several distinctive cysteine motifs necessary for intra and intermolecular disulfide bonding (1,(3)(4)(5)(6) as well as a cytoplasmic C-terminal region.…”

mentioning

confidence: 99%

Calcium-Dependent Association of Calmodulin with the C-Terminal Domain of the Tetraspanin Protein Peripherin/rds

et al. 2007

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Peripherin/rds (p/rds), an integral membrane protein from the transmembrane 4 (TMF4) superfamily, possesses a multi-functional C-terminal domain that plays crucial roles in rod outer segment (ROS) disk renewal and structure. Here, we report that the calcium binding protein calmodulin (CaM) binds to the C-terminal domain of p/rds. Fluorescence spectroscopy reveals Ca 2+ -dependent association of CaM with a polypeptide corresponding to the C-terminal domain of p/rds. The fluorescence anisotropy of the polypeptide upon CaM titration yields a dissociation constant (K D ) of 320 ± 150 nM. The results of the fluorescence experiments were confirmed by GST-pull down analyses in which a GST-p/rds C-terminal domain fusion protein was shown to pull down CaM in a calcium-dependent manner. Moreover, molecular modeling and sequence predictions suggest that the CaM binding domain resides in a p/rds functional hot spot, between residues E314 and G329. Predictions were confirmed by peptide competition studies and a GSTp/rds C-terminal domain construct in which the putative Ca 2+ /CaM binding site was scrambled. This GST-polypeptide did not associate with Ca 2+ /CaM. This putative calmodulin domain is highly conserved between human, mouse, rat, and bovine p/rds. Finally, the binding of Ca 2+ /CaM inhibited fusion between ROS disk and ROS plasma membranes as well as p/rds C-terminaldomain-induced fusion in model membrane studies. These results offer a new mechanism for the modulation of p/rds function.Photoreceptor peripherin/rds (p/rds 1 ) and the non-glycosylated homologue ROM-1 belong to a growing and increasingly complex family of proteins, the tetraspanins (also known as the TMF4 (transmembrane 4 superfamily)) (1, 2). P/rds shares 41% sequence homology

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How to Predict Disorder in a Protein of Interest

Uversky

2016

Methods in Molecular Biology

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Currently available computational tools, which are many, provide a researcher with the multitude of options for prediction of intrinsic disorder in a protein of interest and for finding at least some of its disorder-based functions. This chapter provides a highly subjective guideline on how not to be lost in the "dark forest" of available tools for the analysis of intrinsic disorder. By no means it gives a unique pathway through this forest, but simply presents some of the tools the author uses in his everyday research.

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Predicted and Measured Disorder in Peripherin/rds, a Retinal Tetraspanin

Cited by 23 publications

References 43 publications

Membrane curvature generation by a C-terminal amphipathic helix in peripherin-2/rds, a tetraspanin required for photoreceptor sensory cilium morphogenesis

Membrane curvature generation by a C-terminal amphipathic helix in peripherin-2/rds, a tetraspanin required for photoreceptor sensory cilium morphogenesis

Calcium-Dependent Association of Calmodulin with the C-Terminal Domain of the Tetraspanin Protein Peripherin/rds

How to Predict Disorder in a Protein of Interest

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