Structural and functional relationships between photoreceptor tetraspanins and other superfamily members

Abstract

The two primary photoreceptor-specific tetraspanins are retinal degeneration slow (RDS) and rod outer segment membrane protein-1 (ROM-1). These proteins associate together to form different complexes necessary for the proper structure of the photoreceptor outer segment rim region. Mutations in RDS cause blinding retinal degenerative disease in both rods and cones by mechanisms that remain unknown. Tetraspanins are implicated in a variety of cellular processes and exert their function via the formation of tetraspanin-enriched microdomains. This review focuses on correlations between RDS and other members of the tetraspanin superfamily, particularly emphasizing protein structure, complex assembly, and post-translational modifications, with the goal of furthering our understanding of the structural and functional role of RDS and ROM-1 in outer segment morphogenesis and maintenance, and our understanding of the pathogenesis associated with RDS and ROM-1 mutations.

PRPH2/RDS and ROM-1: Historical context, current views and future considerations

“…In the D2 loop, the two proteins share a 15-16 residue highly conserved cysteine and proline rich region which is thought to promote a conserved 3D structure in the D2 loop, although ROM-1 lacks the N-glycosylation site and an important glutamic acid in the fourth transmembrane domain found in PRPH2/RDS (Bascom et al, 1992; Goldberg et al, 2007; Moritz and Molday, 1996). Both PRPH2/RDS and ROM-1 are members of the tetraspanin super family of proteins which are defined by this conserved tertiary architecture, although PRPH2/RDS and ROM-1 are both functionally distinct from other tetraspanin proteins (Conley et al, 2012b). …”

“…The first observation related to the PRPH2/RDS gene was that it was important for the survival of rod and cone photoreceptor cells of the neural retina in mice (van Nie et al, 1978). This critical importance of PRPH2/RDS would eventually be expanded to include the photoreceptors of all vertebrates (Conley et al, 2012b). Photoreceptors form the outermost neuronal layer in the retina and are the light sensitive cells which initiate phototransduction.…”

Retinal Degeneration Slow (RDS) Glycosylation Plays a Role in Cone Function and in the Regulation of RDS·ROM-1 Protein Complex Formation

“…One of the features of RDS that has stood out as a potential modulator of RDS function in rods versus cones is the N-linked glycosylation at asparagine 229 in the D2 loop. This posttranslational modification is conserved between all examined RDS genes and is markedly absent from ROM-1 (8). The glycosylation site on RDS is located within the critical oligomer-forming domain of RDS, suggesting that it could play a role in modulating the ability of RDS to form important complexes in rods or cones.…”

“…The RDS/PRPH2 gene codes for a photoreceptor-specific glycoprotein called retinal degeneration slow (RDS 2 or peripherin-2), which is a member of the tetraspanin family of proteins and is critical for the proper formation of both rod and cone photoreceptor outer segments (OSs) (1)(2)(3)(4)(5)(6)(7)(8). The OS is an organelle comprising a series of flattened opsin-packed discs and is specialized to detect incoming light and initiate phototransduction (9 -11).…”

“…The RDS protein itself is a small (ϳ35-kD) glycosylated fourpass transmembrane protein that localizes to the rim region of rod discs and the equivalent cone lamellae (8,23). Its N-and C-terminal domains are cytosolic, whereas its two extracellular loop domains (D1 and D2) project into the enclosed discs in rods and the extracellular space between lamellae in cones (24).…”