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Integral membrane protein biosynthesis: why topology is hard to predict

¹ Program in Biological Sciences, University of California, San Francisco, CA 94143-0444, USA
² Department of Physiology, University of California, San Francisco, CA 94143-0444, USA
³ Department of Medicine, University of California, San Francisco, CA 94143-0444, USA

View larger version (12K): [in a new window]   Fig. 1. Types of integral membrane protein. Integral membrane proteins can be synthesized in many different forms. Shown here are a type I integral membrane protein, a type II integral membrane protein, a C-terminally anchored integral membrane protein, a type II signal-anchored protein and a multi-spanning membrane protein.

View larger version (21K): [in a new window]   Fig. 2. The translocon. Two views of the translocon are shown. Sec61 (shown in red) is a heterotrimer and makes up the core of the translocon. TRAM (shown in green) is tightly associated with the translocon and is required for the translocation of many substrates. Other complexes associated with the translocon are signal peptidase (SP; shown in black) and oligosaccharyl transferase (OST; shown in blue).

View larger version (13K): [in a new window]   Fig. 3. Examples of intra-protein interactions necessary for proper biosynthesis. (A) Weak integrators are TM domains that require association with an adjacent TM domain to integrate into the lipid bilayer. Increasing the length of the loop between the two TM domains (as shown on the right) prevents the necessary interactions (shown as zigzag lines) from occurring, possibly because the first TM domain integrates before the necessary interactions can take place (Ota et al., 2000). (B) A strong orientation effector (shown here as a red region) forces TM orientation and integration of adjacent domains that would not integrate independently (purple region).

View larger version (9K): [in a new window]   Fig. 4. Comparison of the experimentally determined and predicted topology of band 3. Band 3 is a polytopic membrane protein that has an N-terminal cytosolic domain. In the diagram, the TM domain is represented as a rectangle and the number of predicted TM domains is indicated for each. The topology of band 3 has been extensively experimentally characterized (Popov et al., 1997; Tanner, 1997; Ota et al., 1998a). Three types of prediction methods are represented: the hydropathy index (Kyte and Doolittle, 1982); the Dense Alignment Surface (DAS) method (Cserzo et al., 1997); and two hidden Markov model (HMM) methods, TMHMM (Tusnady and Simon, 1998; Tusnady and Simon, 2001) and HMMTOP (Sonnhammer et al., 1998). For reference, the location of the first and tenth TM domains of the experimentally determined topology are indicated by vertical dotted lines.