FIGURE 3.

Types of ER membrane proteins and their biogenesis. (A,B) The cartoons depict a signal peptide (SP) and six classes of ER membrane proteins (MP, underlined) with their particular membrane protein type and the respective mechanism of ER targeting and membrane insertion (both indicated below the cartoon in red). Cleavable SPs (in yellow) have a tripartite structure and facilitate ER import of secretory proteins (in green), glycosylphosphatidylinositol (GPI)-anchored- and single-spanning type I membrane proteins (in green). In addition, they may mediate ER import of certain multi-spanning membrane proteins, but not of hairpin, single-spanning type II or III, other multi-spanning and TA membrane proteins, which depend on transmembrane helices (TMHs) that serve as SPs and facilitate membrane targeting as well as insertion. Positively charged amino acid residues (+) play an important role in the orientation of membrane proteins and SPs in the membrane; typically, the orientation follows the positive inside rule. In the case of membrane proteins with amino-terminal TMHs, membrane insertion typically involves the same components and mechanisms, which deliver secretory proteins and GPI-anchored membrane proteins to the ER lumen. In certain cases, however, auxiliary membrane protein insertases, such as EMC or TMCO1 complex may be involved. Following their ER import, GPI-anchored membrane proteins become membrane anchored via their carboxy-termini by GPI-attachment. Some key references are given. The Figure and Figure legend were adapted from Sicking et al. (2021a). C, carboxy-terminus; N, amino-terminus.