THE BETA-SUBUNIT OF THE SIGNAL RECOGNITION PARTICLE RECEPTOR IS A TRANSMEMBRANE GTPASE THAT ANCHORS THE ALPHA-SUBUNIT, A PERIPHERAL MEMBRANE GTPASE, TO THE ENDOPLASMIC-RETICULUM MEMBRANE

The signal recognition particle receptor (SR) is required for the cotr anslational targeting of both secretory and membrane proteins to the e ndoplasmic reticulum (ER) membrane. During targeting, the SR interacts with the signal recognition particle (SRP) which is bound to the sign al sequence of the nascent protein chain. This interaction catalyzes t he GTP-dependent transfer of the nascent chain from SRP to the protein translocation apparatus in the ER membrane. The SR is a heterodimeric protein comprised of a 69-kD subunit (SR alpha) and a 30-kD subunit ( SR beta) which are associated with the ER membrane in an unknown manne r. SR alpha and the 54-kD subunit of SRP (SRP54) each contain related GTPase domains which are required for SR and SRP function. Molecular c loning and sequencing of a cDNA encoding SR beta revealed that SR beta is a transmembrane protein and, like SR alpha and SRP54, is a member of the GTPase superfamily. Although SR beta defines its own GTPase sub family, it is distantly related to ARF and Sari. Using UV cross-linkin g, we confirm that SR beta binds GTP specifically. Proteolytic digesti on experiments show that SR alpha is required for the interaction of S RP with SR. SR alpha appears to be peripherally associated with the ER membrane, and we suggest that SR beta, as an integral membrane protei n, mediates the membrane association of SR alpha. The discovery of its guanine nucleotide-binding domain, however, makes it likely that its role is more complex than that of a passive anchor for SR alpha. These findings suggest that a cascade of three directly interacting GTPases functions during protein targeting to the ER membrane.