Cyclophilin-related protein RanBP2 acts as chaperone for red/green opsin

CYCLOPHILINS are ubiquitous and abundant proteins that exhibit peptidyl prolyl cis-trans isomerization (PPlase) activity in vitro(1,2). Their functions in vivo, however, are not well understood. Two new retinal cyclophilin isoforms, types I and II, are highly expressed in cone photoreceptors of the vertebrate retina(3). Type-II cyclophilin is identical to RanBP2, a large protein that binds the GTPase Ran(4,5). Here we report that two contiguous domains in RanBP(2), Ran binding domain 4 (RBD4) and cyclophilin, act in concert as a chaperone for the opsin molecule of the red/green-sensitive visual pigment of a dichromatic vertebrate. In Drosophila, the cyclophilin NinaA(6,7) is expressed in all photoreceptors(8) and is required for the expression of only a subset of opsins(8,9). The molecular basis of these photoreceptor class-specific effects and the functions of NinaA and other cyclophilins in vivo remain unclear(10). Unlike NinaA, which forms a stable complex with opsin from retinular cells R1-6(11) we find that the cyclophilin domain of RanBP2 does not bind opsin directly; rather, it augments and stabilizes the interaction between red/green (R/G) opsin and the RBD4 domain. This involves a cyclophilin-mediated modification of R/G opsin, possibly involving proline isomerization. The RBD4-cyclophilin supradomain of RanBP2, therefore, is a form of vertebrate chaperone of defined substrate specificity, which may be involved in the processing and/or transport of long-wavelength opsin in cone photoreceptor cells.