Integral membrane protein biosynthesis

Understanding the details of integral membrane protein biogenesis is important for the study of any process or pathway that involves these proteins, including signaling cascades, vesicle trafficking and intercellular communication. Structural information is commonly used to predict protein function, and an important feature of the tertiary structure of an integral membrane protein is its topology or its distribution relative to the membrane. Very few integral membrane proteins have had their topology determined experimentally, however, and of those proteins examined, several exhibit topological heterogeneity. That is, polypeptides with identical sequences can span the membrane differently. Researchers therefore commonly rely on topology prediction algorithms, which we will discuss after reviewing the details of biosynthesis. Although these algorithms are helpful for providing a first approximation, they are often imprecise and sometimes predict incorrect topology (see below). An appreciation of the complexity of integral membrane protein biosynthesis empowers scientists to think more critically about a variety of problems: when the data does not exactly fit the model, an alternate topological form may be part of the explanation. Here we focus on the biosynthesis of mammalian integral membrane proteins that use one or more α-helical membranespanning domains to integrate into the lipid bilayer. Some integral membrane proteins have a single membrane-spanning domain (bitopic), others have several (polytopic). Bitopic membrane proteins are categorized according to the properties of their transmembrane (TM) domains (Fig. 1). During biogenesis, the N-terminus of a type I integral membrane protein is in the ER lumen, whereas in a type II integral membrane protein the N-terminus is in the cytoplasm. Integral membrane proteins that use their first transmembrane domain as both a signal sequence and a stop transfer sequence are classified as signal-anchored proteins. C-terminally anchored proteins have a signal-anchored domain at the extreme Cterminus.