As indicated earlier, the RER branch is the second of the two branches involved in the synthesis and sorting of proteins. In this branch, proteins have N-terminal signal peptides and are synthesized on membrane-bound polyribosomes. They are usually translocated into the lumen of the RER prior to further sorting. Certain membrane proteins, however, are transferred directly into the membrane of the ER without reaching its lumen.

Some characteristics of N-terminal signal peptides are summarized in Table 1.

Table1. Some Properties of Signal Peptides Directing Proteins to the ER

There is much evidence to support the signal hypothesis, confirming that N-terminal signal peptides are involved in the process of protein translocation across the ER membrane. For example, mutant proteins containing altered signal peptides in which hydrophobic amino acids are replaced by hydrophilic ones are not inserted into the lumen of the ER. On the other hand, nonmembrane proteins (eg, α-globin) to which signal peptides have been attached by genetic engineering can be inserted into the lumen of the ER, or even secreted.

Translocation of Proteins to the Endoplasmic Reticulum May Be Cotranslational or Posttranslational

Most nascent proteins are transferred across the ER mem brane into the lumen by the cotranslational pathway, so called because the process occurs during ongoing protein synthesis.

The process of elongation of the remaining portion of the protein being synthesized probably facilitates passage of the nascent protein across the lipid bilayer. It is important that proteins be kept in an unfolded state prior to entering the conducting channel—otherwise, they may not be able to gain access to the channel. The pathway involves a number of specialized proteins, including the signal recognition particle (SRP), the SRP receptor (SRP-R), and the translocon. The translocon consists of three membrane proteins (the Sec61 complex) that form a protein-conducting channel in the ER membrane through which the newly synthesized protein may pass. The channel opens only when a signal peptide is present. Closure of the channel when proteins are not being translocated prevents ions such as calcium and other molecules leaking through it, causing cell dysfunction. The process proceeds in five steps summarized as follows and in Figure1.

Fig1. Cotranslational targeting of secretory proteins to the ER. Step 1:As the signal sequence emerges from the ribosome, it is recognized and bound by the signal recognition particle (SRP) and translation is arrested. Step 2:The SRP escorts the complex to the ER membrane where it binds to the SRP receptor. Step 3:The SRP is released, the ribosome binds to the translocon, translation resumes, and the signal sequence is inserted into the membrane channel.Step 4:The signal sequence opens the translocon and the growing polypeptide chain is translocated across the membrane.Step 5:Cleavage of the signal sequence by signal peptidase releases the polypeptide into the lumen of the ER. (Reproduced with permission from Cooper GM, Hausman RE:The Cell: A Molecular Approach, 6th ed. Sunderland, MA: Sinauer Associates, Inc, 2013.)

Step 1: The signal sequence emerges from the ribosome and binds to the SRP. The SRP containssix proteins associated with an RNA molecule, and each of these plays a role (eg, binding of another molecule) in its function. This step temporarily stops further elongation of the polypeptide chain (elongation arrest) after some 70 amino acids have been polymerized.

Step 2: The SRP-ribosome-nascent protein complex travels to the ER membrane, where it binds to the SRP-R, an ER membrane protein composed of two subunits. The α subunit (SRP-Rα) binds the SRP complex and the mem brane-spanning β subunit (SRP-Rβ) anchors SRP-Rα in the ER membrane. The SRP guides the complex to the SRP-R, preventing premature expulsion of the growing polypeptide into the cytosol.

Step 3: The SRP is released, translation resumes, the ribosome binds to the translocon (Sec 61 complex), and the signal peptide inserts into the channel in the translocon. SRP and both subunits of the SRP-R bindGTP, this enables their interaction, resulting in the hydrolysis of GTP.

Step 4: The signal peptide induces opening of the channel in the translocon, by causing the plug (shown at the bottom on the translocon in Figure 1) to move. The growing polypeptide is then fully translocated across the membrane, driven by its ongoing synthesis.

Step 5: Cleavage of the signal peptide by signal peptidase occurs, and the fully translocated polypeptide/protein is released into the lumen of the ER. The signal peptide is degraded by proteases. Ribosomes are released from the ER membrane and dissociate into their two types of subunits.

Secretory proteins and soluble proteins destined for organelles distal to the ER completely traverse the mem brane bilayer and are discharged into the lumen. Many secretory proteins are N-glycosylated. N-Glycan chains, if present, are added by the enzyme oligosaccharide:protein transferase as these proteins traverse the inner part of the ER membrane—a process called cotranslational glycosylation. Subsequently, these glycoproteins are found in the lumen of the Golgi apparatus, where further changes in glycan chains occur prior to intracellular distribution or secretion.

In contrast, proteins destined to be embedded in mem branes of the ER or in other membranes along the secretory pathway only partially translocate across the ER membrane (steps 1−4). They are able to insert into the ER membrane by lateral transfer through the wall of the translocon.

Posttranslational translocation of proteins to the ER does occur in eukaryotes, although it is less common than the cotranslational route. The process (Figure 2) involves the Sec61 translocon complex, the Sec62/Sec63 complex which is also membrane bound, and chaperone proteins of the Hsp70 family. Some of these prevent the protein folding in the cytosol, but one of them, binding immunoglobulin protein (BiP) (also known as GRP78 or Hsp70), is inside the ER lumen. The protein to be translocated initially binds to the translocon, and cytosolic chaperones are released. The leading end of the peptide then binds to BiP in the lumen. ATP bound to BiP interacts with Sec62/63, ATP is hydrolyzed to ADP providing energy to move the protein forwards, while the bound BiP ADP prevents its moving backward into the cytosol. It can then be pulled through by sequential binding of BiP molecules and ATP hydrolysis. When the entire protein has entered the lumen, ADP is exchanged for ATP, allowing BiP to be released. In addition to its function in protein sorting to the ER lumen, BiP promotes proper folding by preventing aggregation and will temporarily bind abnormally folded immunoglobulin heavy chains and many other proteins, preventing them from leaving the ER.

Fig2. Posttranslational translocation of proteins into the ER. 1. Proteins synthesized in the cytosol are prevented from folding by chaperone proteins such as members of the Hsp70 family. The N-terminal signal sequence inserts into the Sec61 translocon complex and the cytosolic chaperones are released. Binding immu noglobulin protein (BiP) interacts with the protein and the Sec62/63 complex and the bound ATP is hydrolyzed to ADP. 2. The protein is prevented from moving back into the cytosol by the bound BiP, and successive binding of BiP and ATP hydrolysis pulls the protein into the lumen. 3. When the whole protein is inside, ADP is exchanged for ATP and BiP is released.

There is evidence that the ER membrane is involved in retrograde transport of various molecules from the ER lumen to the cytosol. These molecules include unfolded or misfolded glycoproteins, glycopeptides, and oligosaccharides. At least some of these molecules aredegraded in proteasomes. The involvement of the translocon in retrotranslocation is not clear; one or more other channels may be involved. Whatever the case, there is two-way traffic across the ER membrane.

اخر الاخبار

اخبار العتبة العباسية المقدسة

قسم حفظ النظام ينهي استعداداته الخاصة بحفل تخرج طالبات الجامعات العاشر

العتبة العباسية المقدسة تنشر أكاليل الزهور ومظاهر الفرح بمناسبة ذكرى ولادة أمير المؤمنين (عليه السلام)

مجمع الشيخ الكليني يواصل تحضيراته لاستقبال المشاركات في حفل تخرج طالبات الجامعات العاشر

وصول المشاركات في فعاليات مهرجان روح النبوة الثقافي النسوي العالمي الثامن إلى كربلاء

المزيد

الآخبار الصحية

ماذا يحدث لجسمك عند تناول الوجبات السريعة يوميا؟

لصحة عظام المرأة.. الشاي أفضل أم القهوة؟

لبناء العضلات وإنقاص الوزن.. ما أفضل توقيت لتناول البيض؟

أطعمة صحية تساعد على التعافي من "الإنفلونزا الخارقة"

المزيد

الآخبار التكنلوجية

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

تجربة جديدة: الأسفلت المدعوم بالطحالب يقاوم الحفر ويقلل الانبعاثات الكربونية

تسريبات تكشف ملامح أول هاتف قابل للطي من "أبل"

رصد نوع نادر من القطط في تايلاند للمرة الأولى منذ عقود

المزيد

مواضيع ذات صلة

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

Glycoproteins Contain Several Types of O-Glycosidic Linkages

There are Three major classes of Glycoproteins

Biochemical Markers of Bone Remodeling in Postmenopausal Osteoporosis