Protein Sorting II: Endomembrane System
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Questions and Answers

What happens to proteins that are improperly folded and fail to exit the ER?

  • They are routed for degradation. (correct)
  • They remain in the ER indefinitely.
  • They are restored to their original state.
  • They are exported to the Golgi apparatus.

Up to 50% of proteins are estimated to be destroyed due to improper folding.

False (B)

What role does N-glycosylation play in protein quality control?

It serves as a tag to mark the state of protein folding.

What is the primary role of Lumacaftor?

<p>It acts as a chaperone during protein folding. (C)</p> Signup and view all the answers

Median age for people with cystic fibrosis has increased to 40+ years due to new treatments.

<p>True (A)</p> Signup and view all the answers

Defects in the stringency of the ER quality control mechanism lead to __________ disease.

<p>cystic fibrosis</p> Signup and view all the answers

Match the following proteins or processes with their descriptions:

<p>Calnexin = Helps fold newly synthesized proteins Mannosidase = Removes mannoses from misfolded proteins Correctors = Target partial function mutant channels Unfolded Protein Response = Triggers degradation of misfolded proteins</p> Signup and view all the answers

What structure do lipids and proteins move to after the endoplasmic reticulum (ER) for further processing?

<p>Golgi complex</p> Signup and view all the answers

What is the primary function of Rough ER?

<p>Protein synthesis, folding, and glycosylation (A)</p> Signup and view all the answers

Vesicle transport is the method of transportation within the ______ system.

<p>endomembrane</p> Signup and view all the answers

The nuclear envelope is separate from the Endoplasmic Reticulum.

<p>False (B)</p> Signup and view all the answers

Match the following processes to their descriptions:

<p>Vesicle Transport = Method of transportation within the endomembrane system Lumacaftor = Corrector that aids in protein folding Golgi complex = Further processes lipids and proteins Cystic fibrosis treatment advancements = Increased median age for affected individuals</p> Signup and view all the answers

What synthesizes most lipids and cholesterol within the cell?

<p>Smooth ER</p> Signup and view all the answers

The tubular structure of the ER is more abundant near the __________ and is involved in steroid hormone synthesis.

<p>cell edges</p> Signup and view all the answers

Match the following functions with the correct type of ER:

<p>a) Synthesis of phospholipids and cholesterol = Smooth ER b) Synthesis of secreted proteins and proteins of the endomembrane system = Rough ER c) Protein folding and modifications: glycosylation, addition of disulfide bonds = Rough ER d) Synthesis of steroid hormones = Smooth ER e) Detoxification of hydrophobic drugs = Smooth ER</p> Signup and view all the answers

What is the primary mechanism for proteins entering the endoplasmic reticulum?

<p>Co-translational import (A)</p> Signup and view all the answers

The ER import signal is recognized by a signal recognition particle that initiates protein synthesis.

<p>False (B)</p> Signup and view all the answers

What is the role of the signal sequence in protein targeting to the ER?

<p>It starts the transfer of the polypeptide into the ER.</p> Signup and view all the answers

Proteins synthesized for the ER include soluble proteins and ________ membrane proteins.

<p>integral</p> Signup and view all the answers

What is the main function of the Signal Recognition Particle (SRP)?

<p>Recognizing ER import signals (B)</p> Signup and view all the answers

The SRP system is not conserved in prokaryotes.

<p>False (B)</p> Signup and view all the answers

Match the following components with their corresponding functions:

<p>Signal Recognition Particle (SRP) = Binds to the ER import signal Ribosome = Synthesizes polypeptides Synthesis Channel = Translocates proteins into the ER Translocation Channel = Facilitates protein entry into the ER</p> Signup and view all the answers

If a protein has conflicting signal sequences for import into the nucleus and the ER, which signal is likely to prevail?

<p>ER import signal (B)</p> Signup and view all the answers

What triggers the conformation change in SRP when it binds to the ER import signal?

<p>Binding to the ER import signal sequence</p> Signup and view all the answers

The pause domain of SRP blocks __________ from binding to the ribosome.

<p>elongation factor</p> Signup and view all the answers

Soluble proteins are synthesized and directly released into the cytoplasm.

<p>False (B)</p> Signup and view all the answers

Match the following components with their functions:

<p>SRP = Pauses translation SRP receptor = Binds to the ribosome Translocation channel = Facilitates protein entry into the ER Signal sequence = Opens the translocation channel</p> Signup and view all the answers

What happens to the translation process while the SRP brings the ribosome to the ER membrane?

<p>Translation pauses.</p> Signup and view all the answers

What happens to SRP after cargo is delivered and GTP hydrolysis occurs?

<p>It is released and returns to its original shape (A)</p> Signup and view all the answers

The entire SRP complex docks with SRP receptor on the mitochondria.

<p>False (B)</p> Signup and view all the answers

SRP is composed of six polypeptides and one __________ molecule.

<p>RNA</p> Signup and view all the answers

What is the role of the start-transfer signal sequence?

<p>To anchor the protein in the lipid bilayer (A)</p> Signup and view all the answers

The basic part of internal start-transfer sequences is always oriented towards the C-terminus.

<p>False (B)</p> Signup and view all the answers

What modification do most proteins synthesized in the rough ER undergo?

<p>Glycosylation</p> Signup and view all the answers

The signal sequence that helps retain proteins in the ER is known as ______.

<p>KDEL</p> Signup and view all the answers

Match the following roles with their corresponding proteins or enzymes:

<p>Chaperones = Help with protein folding Glycosyl transferase = Adds sugars to proteins Protein disulphide isomerase = Forms disulphide bonds Calnexin = Binds to N-glycosylated proteins</p> Signup and view all the answers

What is the effect of N-glycosylation on proteins?

<p>It promotes folding and serves as a marker of proper folding (C)</p> Signup and view all the answers

Single pass transmembrane proteins have only start-transfer signals.

<p>False (B)</p> Signup and view all the answers

What role do ER chaperones like calnexin play in relation to N-glycosylated proteins?

<p>They assist in protein folding.</p> Signup and view all the answers

Translocated polypeptide chains are folded and glycosylated in the ______ of the rough ER.

<p>lumen</p> Signup and view all the answers

What is a basic characteristic of pairs of start and stop transfer signals?

<p>They dictate the integration of transmembrane proteins into the lipid bilayer. (C)</p> Signup and view all the answers

What is the main function of Smooth ER?

<p>Synthesis of lipids and cholesterol (C), Detoxification of hydrophobic drugs (D)</p> Signup and view all the answers

Rough ER is characterized by its tubular structure.

<p>False (B)</p> Signup and view all the answers

What is the role of the nuclear envelope in relation to the endoplasmic reticulum?

<p>It is part of the endoplasmic reticulum and its lumen is continuous with the ER lumen.</p> Signup and view all the answers

Most intracellular Ca2+ is stored in the ______ ER.

<p>smooth</p> Signup and view all the answers

What sequence is crucial for docking ribosomes at translocation channels in the ER membrane?

<p>Start transfer sequence (A)</p> Signup and view all the answers

Ribosomes are docked at the ER membrane before protein synthesis begins.

<p>False (B)</p> Signup and view all the answers

What role does the signal recognition particle (SRP) play in protein synthesis?

<p>The SRP binds to the ER import signal and pauses translation to bring the ribosome to the ER membrane.</p> Signup and view all the answers

Which signal sequence is likely to prevail when conflicting signals for ER import and mitochondrial import are present?

<p>ER import signal (C)</p> Signup and view all the answers

Integral membrane proteins are only partially translocated and embedded in the ER membrane.

<p>True (A)</p> Signup and view all the answers

What happens to translation when the SRP binds to the ER import signal?

<p>Translation pauses.</p> Signup and view all the answers

The GTP hydrolysis process of SRP does not affect its ability to release the cargo once delivered.

<p>False (B)</p> Signup and view all the answers

What triggers the conformational change in the SRP when it binds to the ER import signal?

<p>Binding to the ER import signal sequence</p> Signup and view all the answers

Match the following components of the SRP system with their functions:

<p>SRP receptor = Facilitates docking with ribosome GTP hydrolysis = Releases SRP and SRP receptor Pause domain = Blocks elongation factor binding Binding pocket = Accommodates hydrophobic ER signals</p> Signup and view all the answers

What happens to the translocation channel when the ribosome is properly docked?

<p>It opens for signal sequence release (B)</p> Signup and view all the answers

The SRP system is conserved across prokaryotes and eukaryotes.

<p>True (A)</p> Signup and view all the answers

What is the result of the SRP binding to the signal sequence?

<p>Translation is paused</p> Signup and view all the answers

What is the consequence of proteins that are misfolded and left unresolved in the ER for too long?

<p>They are routed for degradation. (D)</p> Signup and view all the answers

Only properly folded proteins are allowed to leave the ER.

<p>True (A)</p> Signup and view all the answers

What role does mannosidase play in the lifecycle of misfolded proteins?

<p>Mannosidase removes mannoses from proteins that remain unfolded for too long.</p> Signup and view all the answers

Defects in the ER quality control mechanism are a leading cause of __________ disease.

<p>cystic fibrosis</p> Signup and view all the answers

Match the roles with their corresponding entities:

<p>Calnexin = Assists in the folding of N-glycosylated proteins Correctors = Block unfolded protein response Mannosidase = Removes mannoses from improperly folded proteins N-glycosylation = Marks the state of protein folding</p> Signup and view all the answers

What is the primary function of Lumacaftor in the treatment of cystic fibrosis?

<p>Acts as a corrector to assist in proper protein folding. (A)</p> Signup and view all the answers

Vesicle transport is used to move lipids and proteins from the Golgi complex back to the ER.

<p>False (B)</p> Signup and view all the answers

What is the median age now for people living with cystic fibrosis due to new treatments?

<p>40+ years</p> Signup and view all the answers

Lipids and proteins exit the ER to move to the ______ complex for further processing.

<p>Golgi</p> Signup and view all the answers

Match the following components to their descriptions:

<p>Vesicle transport = Method of transportation within the endomembrane system Lumacaftor = Corrector acting during protein folding Golgi complex = Processing and packaging center for proteins Endoplasmic Reticulum = Site of protein and lipid synthesis</p> Signup and view all the answers

What is the role of start-transfer sequences in proteins?

<p>They anchor proteins in the lipid bilayer. (D)</p> Signup and view all the answers

Internal signal sequences are cleaved after the protein is integrated into the membrane.

<p>False (B)</p> Signup and view all the answers

What modification helps in the folding of proteins in the rough ER?

<p>N-glycosylation</p> Signup and view all the answers

Proteins that need to remain in the ER contain the retention signal ______.

<p>KDEL</p> Signup and view all the answers

Which part of an internal start-transfer sequence is typically oriented toward the N-terminus?

<p>Basic part (C)</p> Signup and view all the answers

Proteins synthesized in the rough ER are typically not glycosylated.

<p>False (B)</p> Signup and view all the answers

What structure is associated with multi-pass transmembrane proteins?

<p>Pairs of start and stop transfer signals</p> Signup and view all the answers

The process by which sugars are added to proteins in the ER is known as ______.

<p>glycosylation</p> Signup and view all the answers

Match the types of transmembrane proteins:

<p>Single pass transmembrane protein = Contains one start-transfer signal Multi pass transmembrane protein = Contains multiple start and stop transfer signals Glycosylated protein = Has sugars attached Resident proteins of the ER = Require KDEL signal for retention</p> Signup and view all the answers

Flashcards

Endoplasmic Reticulum (ER)

A network of flattened sacs and branching tubules that are interconnected. It's the gateway to the endomembrane system.

Rough ER

Part of the ER studded with ribosomes. This is where many proteins are synthesized, folded, and modified (like adding sugars).

Smooth ER

Part of the ER lacking ribosomes. It's involved in lipid synthesis, detoxification, and calcium storage.

Protein sorting to the ER

ER is central for transporting proteins and lipids to the Golgi apparatus and further destinations.

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ER-membrane layers

The membrane layers within the ER system are interconnected, forming a continuous network.

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Co-translational import

Proteins enter the endoplasmic reticulum (ER) while being synthesized.

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Signal sequence

A short stretch of hydrophobic amino acids (6-15) that directs proteins to the ER.

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Signal Recognition Particle (SRP)

A molecule that binds to the signal sequence and pauses translation.

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Translocation channel

A protein channel in the ER membrane where proteins are transferred into the ER.

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Soluble proteins

Proteins that are entirely synthesized into the ER lumen.

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Integral membrane proteins

Proteins that are partially transferred to and embedded within the ER membrane.

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Conflicting signal sequences

Proteins with two signal sequences for different compartments (e.g., ER and nucleus).

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ER import signal

The signal sequence indicating a protein should enter the ER.

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ER Quality Control

A system within the ER that ensures only properly folded proteins are exported. This process involves adding and removing sugars to monitor folding status.

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Calnexin Role

Calnexin is an ER chaperone protein that binds to unfolded proteins with terminal glucose. This binding helps with protein folding.

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Mannosidase Function

Mannosidase is an enzyme that removes mannose sugars from unfolded proteins, preventing the addition of glucose and triggering degradation.

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Start-transfer sequence

A signal sequence that initiates the translocation of a protein across the ER membrane.

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Single-pass transmembrane protein

A protein that passes through the ER membrane once.

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Cystic Fibrosis Link

Defects in ER quality control can lead to diseases like cystic fibrosis. Misfolded Cl- channel proteins trigger an unfolded protein response in the ER.

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Correctors in Cystic Fibrosis

Drugs called correctors are being developed to block the unfolded protein response in cystic fibrosis. This might improve function of partially folded proteins.

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Multi-pass transmembrane protein

A protein that passes through the ER membrane multiple times.

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ER retention signal

A specific amino acid sequence that keeps a protein within the ER.

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N-linked glycosylation

Addition of a carbohydrate to a protein in the ER.

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ER chaperones

Proteins that help other proteins fold correctly in the ER.

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Protein folding

The process by which a protein assumes its functional 3D structure in the ER.

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Internal start-transfer sequence

A signal sequence, not at the N-terminus, that directs a protein into the lipid bilayer.

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Protein modification in rough ER

Adding sugars, lipids, and creating disulfide bridges to proteins within the ER.

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SRP's binding pocket

A site on SRP that recognizes and interacts with hydrophobic ER import signals.

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GTP hydrolysis by SRP

The process of breaking down guanosine triphosphate (GTP) by SRP, triggering SRP release from the SRP receptor.

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Ribosome docking on translocator

The precise alignment of the ribosome with the protein translocation channel on the ER membrane, releasing SRP, initiating translation.

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Signal sequence cleavage

The removal of the signal peptide from a protein after it has passed through the ER membrane and into the lumen.

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Translation Pause

A temporary halt in the ribosome's movement along the mRNA molecule to facilitate correct protein targeting to ER membrane.

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Lumacaftor

A drug that helps correct protein folding in cystic fibrosis, improving the function of CFTR channels in the cell membrane.

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CFTR Channel Folding

The process of the cystic fibrosis transmembrane conductance regulator (CFTR) protein folding into its correct shape for proper function. Lumacaftor assists in this process.

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Unfolded Protein Response

A cellular stress response triggered by the accumulation of misfolded proteins in the ER. This response aims to restore normal protein folding or eliminate damaged proteins.

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Vesicle Transport

The process of moving molecules within the cell using small, membrane-bound sacs called vesicles. It's vital for transporting proteins and lipids between different cellular compartments.

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ER to Golgi Transport

The movement of molecules from the endoplasmic reticulum (ER) to the Golgi apparatus, where further processing occurs.

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ER Gateway

The endoplasmic reticulum (ER) serves as the entry point for proteins and lipids destined for other compartments within the endomembrane system.

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Rough ER vs Smooth ER

Rough ER is studded with ribosomes and specializes in protein synthesis, folding, and glycosylation. Smooth ER lacks ribosomes and focuses on lipid and cholesterol synthesis, detoxification, and calcium storage.

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What is Lumacaftor?

Lumacaftor is a drug that acts as a chaperone during protein folding, helping to increase the number of channels that reach the plasma membrane.

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How does Lumacaftor help cystic fibrosis patients?

Lumacaftor helps correct the folding of the CFTR protein, which is faulty in cystic fibrosis. This increases the number of properly functioning channels in the cell membrane.

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What is the Golgi complex?

The Golgi complex is a stack of flattened sacs that further processes lipids and proteins that have exited the ER.

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What is vesicle transport?

Vesicle transport is the process of moving things within the cell using small, membrane-bound sacs called vesicles.

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SRP's Role

The Signal Recognition Particle (SRP) binds to the signal sequence of a protein, pauses translation, and guides the ribosome to the ER membrane for protein import.

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SRP Receptor

A protein on the ER membrane that recognizes and binds SRP, facilitating the docking of the ribosome to the translocation channel.

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Ribosome Docking

The ribosome precisely aligns with the translocation channel on the ER membrane, releasing SRP and allowing protein import to continue.

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SRP's GTP Hydrolysis

SRP uses GTP hydrolysis (breaking down GTP) to release itself from the SRP receptor and revert to its original shape.

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Calnexin and calmodulin

ER chaperone proteins that bind to N-glycosylated proteins with a single terminal glucose, acting as a signal for unfolded proteins.

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Protein modification in the ER

Changes made to proteins in the ER, including glycosylation, lipidation, and disulfide bond formation.

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Study Notes

Protein Sorting II: How Proteins Enter the Endomembrane System

  • The endoplasmic reticulum (ER) is the primary gateway to the endomembrane system.
  • Proteins destined for the ER possess a signal sequence (6-15 hydrophobic amino acids, typically at the N-terminus)
  • mRNA encoding these proteins is targeted to the ER, and ribosomes bind to the ER membrane during translation
  • The process where ribosomes attach and protein synthesis occurs at the ER membrane is called co-translational import.
  • Soluble proteins are synthesized and directed into the ER lumen through a channel.
  • Membrane proteins are partly translocated and integrated into the ER membrane.
  • The SRP (signal recognition particle) recognizes and binds the signal sequence, causing translation to pause.
  • The SRP-ribosome complex then docks with the SRP receptor on the ER membrane, and the ribosome and protein are now attached to translocator on the ER membrane.
  • Translation resumes, and the growing polypeptide chain is threaded through the translocator into the ER lumen.
  • The signal sequence is cleaved by signal peptidase in the ER lumen.
  • The signal sequence is rich in methionine, and accommodates hydrophobic ER import signals.
  • GTP hydrolysis by SRP and SRP receptor releases the SRP and restarts translation.
  • The complete complex docks with the SRP receptor on the ER membrane, and translation resumes.
  • The translocation channel opens in a plug-like fashion permitting proteins to enter the lumen.
  • Disulfide bridges are formed in the ER by PDI.
  • Proteins are glycosylated.
  • GPI anchors can be added.
  • Proper folding of proteins in the ER is monitored.
  • Misfolded proteins are exported to the cytosol for degradation.
  • The ER quality control mechanism ensures that only properly folded proteins are allowed to exit and enter the Golgi apparatus.
  • Proteins needing to remain in the ER have an ER retention signal (KDEL).
  • The ER quality control mechanism estimates that, up to 30% of proteins, are destroyed if the folding is not proper.
  • Defects in the ER quality control are a cause of cystic fibrosis.
  • Lipids and proteins exit the ER, moving to the Golgi apparatus for further processing via vesicle transport.
  • Vesicle transport is used inside the endomembrane system, including from the ER to Golgi.

Rough ER vs. Smooth ER

  • Rough ER:
    • Flattened sheets
    • Coated with ribosomes
    • Synthesizes, folds, and glycosylates proteins.
  • Smooth ER:
    • Tubular
    • Less abundant in most cell types
    • Synthesizes lipids and cholesterol
    • Stores intracellular Ca2+.
    • Detoxifies compounds.
    • Involved in steroid hormone synthesis.

ER Import Signal

  • The ER import signal is recognized by a co-receptor.
  • Co-receptor docks the ribosome at translocators in the ER membrane.
  • The ribosome binds to the ER membrane, and the mRNA is translated.

Signal Recognition Particle (SRP)

  • SRP is an ancient rbonucleoprotein co-receptor.
  • SRP in eukaryotes has 6 polypeptides and 1 RNA molecule.
  • The system evolved early in evolution.
  • SRP has a hinge mechanism.
  • SRP binds to the signal ER import sequence and causes a change in conformation of this sequence, thus triggering a conformational change that exposes a binding site.
  • The SRP receptor is involved in binding to the ribosome complex
  • The pause domain helps block the elongation of translation.
  • SRP serves as a molecular matchmaker.
  • SRP binding pauses translation, so that peptide synthesis does not occur until the protein and ribosome complex are docked properly into the ER.

Modification of Proteins in the rough ER

  • GPI anchors are added to some proteins.
  • Disulfide bridges are formed by PDI, establishing a critical part of the protein structure.
  • Some proteins are glycosylated (N-linked complex oligosaccharides).

N-glycosylation

  • N-glycosylation can promote the folding of certain proteins and thus is used as a "tag" that marks the state of protein folding, as properly folded proteins are able to exit the ER.

Export and Degradation of Misfolded ER Proteins

  • Misfolded proteins are exported to be degraded by proteasomes in the cytosol or other organelles.
  • A signaling chain of ubiquitin marks misfolded proteins for degradation.

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Lecture 14. Protein Sorting II 2024 PDF

Description

Explore how proteins enter the endomembrane system, focusing on the role of the endoplasmic reticulum (ER) and various mechanisms involved, including co-translational import. Understand the complexities of signal sequences, SRP functionality, and the translocation process of proteins. Test your knowledge with this quiz covering key concepts of protein sorting.

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