Glycophorin LDL receptor Influenza HA protein Insulin receptor Growth hormone receptor
Asialoglycoprotein receptor Transferrin receptor Sucrase-isomaltase precursor Golgi galactosyltransferase Golgi sialyltransferase Influenza HN protein
▲ FIGURE 16-10 Major topological classes of integral membrane proteins synthesized on the rough ER. The hydrophobic segments of the protein chain form a helices embedded in the membrane bilayer; the regions outside the membrane are hydrophilic and fold into various conformations. All type IV proteins have multiple transmembrane a helices. The type IV topology depicted here corresponds to that of G
establish the membrane orientation of transmembrane segments, as discussed in the next section.
The proteins forming topological class IV contain multiple membrane-spanning segments (see Figure 16-10). Many of the membrane transport proteins discussed in Chapter 7 and the numerous G protein-coupled receptors covered in Chapter 13 belong to this class, sometimes called multipass proteins. A final type of membrane protein lacks a hydrophobic membrane-spanning segment altogether; instead, these proteins are linked to an amphipathic phospholipid anchor that is embedded in the membrane.
Internal Stop-Transfer and Signal-Anchor Sequences Determine Topology of Single-Pass Proteins
We begin our discussion with the membrane insertion of integral proteins that contain a single, hydrophobic membrane-spanning segment. Two sequences are involved in targeting and orienting type I proteins in the ER membrane, whereas type II and type III proteins contain a single, internal topogenic sequence.
Type I Proteins All type I transmembrane proteins possess an N-terminal signal sequence that targets them to the ER and an internal hydrophobic sequence that becomes the membrane-spanning a helix. The N-terminal signal sequence on a nascent type I protein, like that of a secretory protein,
G protein-coupled receptors (e.g., P-adrenergic receptor) Glucose transporters (e.g., GLUT1) Voltage-gated Ca2+ channels ABC small molecule pumps CFTR (Cl-) channel Sec61 Connexin protein-coupled receptors: seven a helices, the N-terminus on the exoplasmic side of the membrane, and the C-terminus on the cytosolic side. Other type IV proteins may have a different number of helices and various orientations of the N-terminus and C-terminus. [See E. Hartmann et al., 1989, Proc. Nat'l. Acad. Sci. USA 86:5786, and C. A. Brown and S. D. Black, 1989, J. Biol. Chem. 264:4442.]
initiates cotranslational translocation of the protein through the combined action of the SRP and SRP receptor. Once the N-terminus of the growing polypeptide enters the lumen of the ER, the signal sequence is cleaved, and the growing chain continues to be extruded across the ER membrane. However, unlike the case with secretory proteins, a sequence of about 22 hydrophobic amino acids in the middle of a type I protein stops transfer of the nascent chain through the translo-con (Figure 16-11). This internal sequence, because of its hydrophobicity, can move laterally between the protein sub-units that form the wall of the translocon and become anchored in the phospholipid bilayer of the membrane, where it remains. Because of its dual function, this sequence is called a stop-transfer anchor sequence.
Once translocation is interrupted, translation continues at the ribosome, which is still anchored to the now unoccupied and closed translocon. As the C-terminus of the protein chain is synthesized, it loops out on the cytosolic side of the membrane. When translation is completed, the ribosome is released from the translocon and the C-terminus of the newly synthesized type I protein remains in the cytosol.
Support for this model, depicted in Figure 16-11, has come from studies in which cDNAs encoding various mutant receptors for human growth hormone (HGH) are expressed in cultured mammalian cells. The wild-type HGH receptor, a typical type I protein, is transported normally to the plasma membrane. However, a mutant receptor that has charged residues inserted into the a-helical membrane-spanning segment, or that is missing most of this segment, is translocated
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