Human autoantibodies against the 54 kDa protein of the signal recognition particle block function at multiple stages

Both secretory and membrane proteins destined for entry into the eukaryotic secretory pathway carry hydrophobic signal sequences that direct them to the endoplasmic reticulum (ER). The signal sequence is often located towards the amino terminus of the protein, and in the case of presecretory proteins it is proteolytically removed after targeting is completed [1]. These ER targeting signals are recognized and bound by a small ribonucleoprotein complex, the signal recognition particle (SRP), as soon as they emerge from the ribosome during protein synthesis [2-4]. This co-translational binding of SRP causes an arrest or retardation of translation that is relieved upon the interaction of the nascent chain/ribosome/SRP complex with the SRP receptor complex located in the ER membrane [3]. The binding of SRP to the SRP receptor allows the release of the signal sequence from SRP in a process that is dependent upon GTP binding and hydrolysis [3] and that also requires the presence of the Sec61 translocon [5]. Translation of the targeted nascent chain resumes and the free SRP can enter a new cycle of targeting, while the signal sequence inserts into the ER translocon and is cleaved on the luminal side of the membrane by signal peptidase when a suitable site is available [6]Mammalian SRP consists of a 7S RNA and six proteins of molecular weight 9 kDa, 14 kDa, 19 kDa, 54 kDa, 68 kDa and 72 kDa [3]. The SRP 9 kDa and 14 kDa proteins form a heterodimer that is involved in the SRP-mediated translation arrest or retardation [3,7], while the SRP 19 kDa protein facilitates the binding of the 54 kDa subunit of the signal recognition particle (SRP54) to the 7S RNA [3,4]. The SRP54 subunit binds to ER signal sequences via its methionine-rich carboxy-terminal region (M-domain) and interacts with the SRP receptor complex via its central GTP binding domain [3,4]. This latter interaction means that the targeting of nascent polypeptides to the ER membrane is regulated by three GTPases; that