Intracellular protein topogenesis refers to the processes that occur during or shortly after protein synthesis on ribosomes, leading to the unidirectional translocation of proteins across or asymmetric integration into specific cellular membranes, followed by their sorting to other intracellular membranes or compartments. The information for these processes, termed "protein topogenesis," is encoded in discrete "topogenic" sequences within the polypeptide chain. These sequences are either permanent or transient and are shared by structurally diverse proteins that are topologically equivalent, i.e., targeted to the same intracellular address. Four types of topogenic sequences are distinguished: signal sequences, stop-transfer sequences, sorting sequences, and insertion sequences. Signal sequences initiate translocation across specific membranes and are recognized by protein translocators. Stop-transfer sequences interrupt translocation initiated by a signal sequence, leading to asymmetric integration of proteins into translocation-competent membranes. Sorting sequences determine the posttranslocational traffic of proteins between different membranes. Insertion sequences facilitate the unilateral integration of proteins into the lipid bilayer without the need for a protein effector. The evolution of topogenic sequences is linked to the precellular evolution of membranes and compartments. The phylogeny of biological membranes, cells, and compartments is considered in relation to protein topogenesis. The development of translocation mechanisms allowed for the segregation of proteins and the integration of integral membrane proteins into membranes. The posttranslocational pathways involve the sorting of proteins to specific compartments, with sorting sequences playing a key role in this process. The evolution of membranes and compartments is traced back to the precellular stage, with the development of lipid vesicles and the integration of proteins into their outer leaflet. The evolution of eukaryotic membranes is attributed to the endosymbiotic theory, with the plasma membrane of a foreign cell contributing to the formation of xenoplasmic membranes. The posttranslocational pathways involve the sorting of proteins to specific compartments, with sorting sequences playing a key role in this process. The evolution of topogenic sequences is linked to the development of translocation mechanisms and the diversification of protein functions.Intracellular protein topogenesis refers to the processes that occur during or shortly after protein synthesis on ribosomes, leading to the unidirectional translocation of proteins across or asymmetric integration into specific cellular membranes, followed by their sorting to other intracellular membranes or compartments. The information for these processes, termed "protein topogenesis," is encoded in discrete "topogenic" sequences within the polypeptide chain. These sequences are either permanent or transient and are shared by structurally diverse proteins that are topologically equivalent, i.e., targeted to the same intracellular address. Four types of topogenic sequences are distinguished: signal sequences, stop-transfer sequences, sorting sequences, and insertion sequences. Signal sequences initiate translocation across specific membranes and are recognized by protein translocators. Stop-transfer sequences interrupt translocation initiated by a signal sequence, leading to asymmetric integration of proteins into translocation-competent membranes. Sorting sequences determine the posttranslocational traffic of proteins between different membranes. Insertion sequences facilitate the unilateral integration of proteins into the lipid bilayer without the need for a protein effector. The evolution of topogenic sequences is linked to the precellular evolution of membranes and compartments. The phylogeny of biological membranes, cells, and compartments is considered in relation to protein topogenesis. The development of translocation mechanisms allowed for the segregation of proteins and the integration of integral membrane proteins into membranes. The posttranslocational pathways involve the sorting of proteins to specific compartments, with sorting sequences playing a key role in this process. The evolution of membranes and compartments is traced back to the precellular stage, with the development of lipid vesicles and the integration of proteins into their outer leaflet. The evolution of eukaryotic membranes is attributed to the endosymbiotic theory, with the plasma membrane of a foreign cell contributing to the formation of xenoplasmic membranes. The posttranslocational pathways involve the sorting of proteins to specific compartments, with sorting sequences playing a key role in this process. The evolution of topogenic sequences is linked to the development of translocation mechanisms and the diversification of protein functions.