The routes that proteins follow to be inserted into the mem branes of the ER include cotranslational insertion; posttranslational insertion; retention in the GA followed by retrieval to the ER; and retrograde transport from the GA.

Cotranslational Insertion Requires Stop Transfer Sequences or Internal Insertion Sequences

Figure 1 shows a variety of ways in which proteins are dis tributed in membranes. In particular, the amino termini of certain proteins (eg, the low-density lipoprotein [LDL] receptor) can be seen to be on the extracytoplasmic face, whereas for other proteins (eg, the asialoglycoprotein receptor) thecarboxyl termini are on this face. These dispositions are explained by the initial biosynthetic events at the ER membrane. Proteins like the LDL receptor enter the ER membrane in a manner analogous to a secretory protein; they partly traverse the ER membrane, the signal peptide is cleaved, and their amino terminal protrudes into the lumen. However, this type of protein contains a highly hydrophobic segment which acts as a halt- or stop-transfer signal and causes its retention in the membrane (Figure 2). This sequence has its N-terminal end in the ER lumen and the C-terminal in the cytosol; the stop-transfer signal forms the single transmembrane segment of the protein and is its membrane-anchoring domain. The protein is believed to exit the translocon into the membrane by a lateral gate which opens and closes continuously allowing hydrophobic sequences to enter the lipid bilayer.

Fig1. Variations in the way in which proteins are inserted into membranes. This schematic representation illustrates a number of possible orientations. The orientations form initially in the ER membrane, but are retained when vesicles bud off and fuse with the plasma membrane, so that the terminal initially facing the ER lumen always faces the outside of the cell. Type I transmembrane proteins (eg, the LDL receptor and influenza hemagglutinin) cross the membrane once and have their amino termini in the ER lumen/cell exterior. Type II trans membrane proteins (eg, the asialoglycoprotein and transferrin receptors) also cross the membrane once, but have their C-termini in the ER lumen/cell exterior. Type III transmembrane proteins (eg, cytochrome P450, an ER membrane protein) have a disposition similar to type I pro teins, but do not contain a cleavable signal peptide. Type IV transmembrane proteins (eg, G-protein–coupled receptors and glucose transporters) cross the membrane a number of times (7 times for the former and 12 times for the latter); they are also called polytopic membrane proteins. (C, carboxyl terminal; N, amino terminal.)

Fig2. Insertion of a membrane protein with a stop-transfer signal into the ER membrane.The protein enters the membrane in a similar way to a secretory protein, the signal peptide is cleaved as the polypeptide chain crosses the membrane, so the amino terminus of the polypeptide chain is exposed in the ER lumen. However, translocation of the polypeptide chain across the membrane is halted when the translocon recognizes a transmembrane stop-transfer sequence which is highly hydrophobic. The protein then exits the translocon channel via a lateral gate and become anchored in the ER membrane. Continued translation results in a membrane-spanning protein with its carboxy terminus on the cytosolic side. (Reproduced with permission from Cooper GM, Hausman RE: The Cell: A Molecular Approach, 6th ed. Sunderland, MA: Sinauer Associates, Inc, 2013.)

The small patch of ER membrane in which the newly synthesized LDL receptor is located subsequently buds off as a component of a transport vesicle which eventually fuses with the PM so that the C-terminal faces the cytosol and the N-terminal faces the outside of the cell. In contrast, the asialo-glycoprotein receptor lacks a cleavable N-terminal signal peptide, but possesses an internal insertion sequence, which inserts into the membrane but is not cleaved. This acts as an anchor, and its C-terminus is extruded through the membrane into the ER lumen. Cytochrome P450 is anchored in a similar way, but its N-terminal, rather than C-terminal, is extruded into the lumen. The more complex disposition of a trans membrane transporter (eg, for glucose) which may cross the membrane up to 12 times, can be explained by the fact that alternating transmembrane α-helices act as uncleaved insertion sequences and as halt-transfer signals, respectively. Each pair of helical segments is inserted as a hairpin. Sequences that determine the structure of a protein in a membrane are called topogenic sequences. The LDL receptor, asialoglycoprotein receptor, and glucose transporter are examples of types I, II, and IV transmembrane proteins and are found in the PM, while cytochrome P450 is an example of a type III protein which remains in the ER membrane (see Figure 1).

Some Proteins Are Synthesized on Free Polyribosomes & Attach to the Endoplasmic Reticulum Membrane Posttranslationally

 Proteins may enter the ER membrane posttranslationally through the lateral gate in the translocon in a similar way to cotranslationally sorted molecules. An example is cytochrome b5 , which appears to enter the ER membrane subsequent to translation, assisted by several chaperones.

Other Routes Include Retention in the GA With Retrieval to the ER & Also Retrograde Transport From the GA

A number of proteins possess the amino acid sequence KDEL (Lys-Asp-Glu-Leu) at their carboxyl terminal (see Table 49–1). KDEL-containing proteins first travel to the GA in vesicles coated with coat protein II (COPII) (see later). This process is known as anterograde vesicular transport. In the GA, they interact with a specific KDEL receptor protein, which retains them transiently. They thenreturn to the ER in vesicles coated with coat protein I (COPI, retrograde vesicular transport), where they dissociate from the receptor, and are thus retrieved. HDEL sequences (H = histidine) serve a similar purpose. The above processes result in net localization of certain soluble proteins to the ER lumen.

Certain other non-KDEL–containing proteins also pass to the Golgi and then return, by retrograde vesicular trans port, to the ER to be inserted therein. These include vesicle components that must be recycled, as well as certain ER mem brane proteins. These proteins often possess a C-terminal signal located in the cytosol rich in basic residues.

Thus, proteins reach the ER membrane by a variety of routes, and similar pathways are likely to be used for other membranes (eg, the mitochondrial membranes and the PM). Precise targeting sequences have been identified in some instances (eg, KDEL sequences).

The topic of membrane biogenesis is discussed further later in this chapter.

اخر الاخبار

اخبار العتبة العباسية المقدسة

العتبة العباسية المقدسة تواصل عقد مجلس عزائها بذكرى وفاة السيدة زينب (عليها السلام)

جمعية العميد تصدر الكتاب الأول من الموسوعة التربوية في نهج البلاغة

قسم صناعة الشبابيك يباشر أعمال إدامة الشباك القديم لمرقد الإمامين العسكريين (عليهما السلام)

صحن مرقد أبي الفضل العباس (عليه السلام) يشهد إقامة مجلس عزاء بذكرى وفاة السيدة زينب (عليها السلام)

المزيد

الآخبار الصحية

طبيب يكشف أفضل مكمل غذائي لتحسين المزاج ودعم الصحة النفسية

دراسة جديدة تكشف أضرار الأطعمة الجاهزة على القلب ؟

6 أطعمة طبيعية تهدئ الزكام دون أدوية.. تعرف عليهم

ماذا يحدث لأعراض الزكام عند تناول الثوم بانتظام؟

المزيد

الآخبار التكنلوجية

ابتكار ثوري في بطاريات السيارات الكهربائية.. سعة أعلى 4 مرات

ماذا يحدث لجسمك عند شرب الماء الساخن يوميا؟

7 فوائد "خفية" لشرب شاي الكركديه كل يوم

دراسة تكشف قدرة الحيتان على سماع الأصوات منخفضة وعالية التردد من مسافة بعيدة

المزيد

مواضيع ذات صلة

Proteoglycans & Glycosaminoglycans

The ER Functions as The Quality Control Compartment of The Cell

Proteins sorted via the Rough ER branch have N-Terminal signal peptides

Proteins Imported Into Peroxisomes Carry Unique Targeting Sequences

Transport of Macromolecules in & out of the Nucleus Involves Localization Signals

Most Mitochondrial Proteins Are Imported

Many proteins are targeted by signal sequences to their correct destinations

Conjugation reactions in phase 2 metabolism prepare Xenobiotics for excretion

Isoforms of Cytochrome P450 Hydroxylate a Wide Variety of Xenobiotics in Phase 1 Metabolism

Glycans are involved in The Binding of Viruses, Bacteria, & Some Parasites to Human Cells

Glycoproteins are Involved in Many Biological Processes & in Many Diseases

The Biosynthesis of N-Linked Glycoproteins Involves Dolichol-P-P-Oligosaccharide