Proposed models for Spc2-mediated substrate and cleavage site selection. (A and B) The cytosolic domain of Spc2 prevents access of signal sequences with longer n-regions to the TM-window, (B) membrane thinning induced by Spc2 prevents access to signal sequences with longer h-regions to the TM-window. (C) Membrane thinning induced by Spc2 increases the exposure of proximal cleavage sites to the SPC active site (the blue star indicates a proximal cleavage site rendered inaccessible by the absence of Spc2).