Harpers

506 / CHAPTER 46NNNCNCCNNEXTRACYTOPLASMICFACEPHOSPHOLIPIDBILAYERCNVarious transporters (eg, glucose)NInfluenza neuraminidaseAsialoglycoprotein receptorTransferrin receptorHLA-DR invariant chainCC CInsulin andIGF-I receptorsCYTOPLASMICFACECNG protein–coupled receptorsLDL receptorHLA-A heavy chainInfluenza hemagglutininFigure 46–5. Variations in the way in which proteins are inserted into membranes. Thisschematic representation, which illustrates a number of possible orientations, shows the segmentsof the proteins within the membrane as α-helices and the other segments as lines. TheLDL receptor, which crosses the membrane once and has its amino terminal on the exterior, iscalled a type I transmembrane protein. The asialoglycoprotein receptor, which also crosses themembrane once but has its carboxyl terminal on the exterior, is called a type II transmembraneprotein. The various transporters indicated (eg, glucose) cross the membrane a number of timesand are called type III transmembrane proteins; they are also referred to as polytopic membraneproteins. (N, amino terminal; C, carboxyl terminal.) (Adapted, with permission, from Wickner WT,Lodish HF: Multiple mechanisms of protein insertion into and across membranes. Science1985;230:400. Copyright © 1985 by the American Association for the Advancement of Science.)the ER membrane, its signal peptide is cleaved, and itsamino terminal protrudes into the lumen. However, it isretained in the membrane because it contains a highlyhydrophobic segment, the halt- or stop-transfer signal.This sequence forms the single transmembrane segmentof the protein and is its membrane-anchoring domain.The small patch of ER membrane in which the newlysynthesized LDL receptor is located subsequently budsoff as a component of a transport vesicle, probably fromthe transitional elements of the ER (Figure 46–2). Asdescribed below in the discussion of asymmetry of proteinsand lipids in membrane assembly, the dispositionof the receptor in the ER membrane is preserved in thevesicle, which eventually fuses with the plasma membrane.In contrast, the asialoglycoprotein receptor possessesan internal insertion sequence, which inserts intothe membrane but is not cleaved. This acts as an anchor,and its carboxyl terminal is extruded through the membrane.The more complex disposition of the transporters(eg, for glucose) can be explained by the factthat alternating transmembrane α-helices act as uncleavedinsertion sequences and as halt-transfer signals,respectively. Each pair of helical segments is inserted as ahairpin. Sequences that determine the structure of aprotein in a membrane are called topogenic sequences.As explained in the legend to Figure 46–5, the abovethree proteins are examples of type I, type II, and typeIII transmembrane proteins.B. SYNTHESIS ON FREE POLYRIBOSOMES& SUBSEQUENT ATTACHMENT TO THEENDOPLASMIC RETICULUM MEMBRANEAn example is cytochrome b 5 , which enters the ERmembrane spontaneously.C. RETENTION AT THE LUMINAL ASPECTOF THE ENDOPLASMIC RETICULUMBY SPECIFIC AMINO ACID SEQUENCESA number of proteins possess the amino acid sequenceKDEL (Lys-Asp-Glu-Leu) at their carboxyl terminal.