Schematic showing the effect of subdomain-specific autoantibodies on SRP54 function. (a) Autoantibodies against the SRP54G domain inhibit signal-sequence binding. Two conformations for SRP54 have been proposed: one where the signal sequence (S) binding groove of the SRP54M domain is closed (i) and the second where it is open (ii). Autoantibodies directed to the G-domain of SRP54 may prevent the conformational change required to open the signal-sequence binding pocket (iii) . (b) Autoantibodies against the SRP54N or SRP54G domain prevent signal-sequence release from SRP54 and membrane insertion. When SRP54 interacts with the SRP receptor (SR) at the endoplasmic reticulum (ER) membrane, the signal sequence is released from the M-domain and inserts into the Sec61p translocon in the ER membrane (i). In the presence of autoantibodies directed against the SRP54N or SRP54G domain, the signal sequence remains bound to SRP54 (ii and iii). Ribosomes have been omitted from the nascent chains for the sake of simplicity. The diagrammatic representation of the SRP54 subunit in this model is based on our current understanding of its three-dimensional structure [9,44] rather than on the simple linear organization of the three domains presented in Figure 2a.