![]() ![]() Others such as signal peptidase complex, TRAM, or Sec62/63 are present in sub-stoichiometric amounts and may only associate transiently or under certain circumstances when particular substrates are present in the translocon. Accessory protein complexes such as TRAP seems to be involved in membrane protein topogenesis and oligosaccharyltransferase, which adds oligosaccharides to asparagine residues in the lumen of the ER (at NXS/T sequons), are commonly found associated with the translocon core and/or are present in approximately stoichiometric amounts. In addition, numerous accessory proteins are associated with this core complex which may modulate translocon activity or provide functionality that complements its translocation and integrase function. The mammalian Sec61 translocon consists of a core heterotrimeric Sec61α, β, and γ complex which have 10, 1, and 1 transmembrane (TM) domains respectively. ![]() In this article, we will exclusively consider membrane protein assembly mediated by the Sec61 translocon. These integrases have been evolutionary conserved in eukaryotes with some of them, such as Sec61 and Get1/2, having homologs in prokaryotes. A further integrase called the ER membrane protein complex (EMC) is also implicated in post-translational membrane integration of a subset of TA proteins but also seems to play additional roles in co-translational membrane protein assembly. The Sec61 translocon/integrase is the primary integration machinery of the ER although there are others, notably the Get1/Get2 integrase that is responsible for tail-anchored (TA) protein integration. Most integral membrane proteins require proteinaceous machinery known as an integrase for their insertion into the ER. Thus, we will concentrate on the initial folding and assembly of proteins into the ER membrane and not their subsequent cellular distribution. The signals and machineries that direct complex endomembrane trafficking pathways are beyond the scope of this article. Following this assembly, these proteins are distributed to their intended destinations via specific trafficking pathways. The majority of, if not all, integral membrane proteins distributed throughout the endomembrane network in eukaryotic cells first assemble into the endoplasmic reticulum (ER) membrane. We will address questions such as: Where do the stretches of amino acids fold into a helical conformation? What is/are the route/routes that these stretches take from synthesis at the ribosome to integration through the ER translocon? How do these stretches ‘know’ to integrate and in which orientation? How do marginally hydrophobic stretches of amino acids integrate and survive as transmembrane helices? In this review, we will consider how transmembrane helices achieve membrane integration. These stretches are typically around 20 amino acids long and are known as transmembrane (TM) helices. It is generally accepted that to exist in this non-aqueous environment the majority of membrane integrated amino acids are primarily non-polar/hydrophobic and adopt an α-helical conformation. Some of these proteins are completely translocated into the lumen of the ER while others integrate stretches of amino acids into the greasy 30 Å wide interior of the ER membrane bilayer. In eukaryotic cells, the endoplasmic reticulum (ER) is the entry point for newly synthesized proteins that are subsequently distributed to organelles of the endomembrane system.
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