The ubiquitin-proteasome mediated protein degradation pathway | Ubiquitin ligase | Proteasome

Summary

This video script explains the ubiquitin proteasome pathway, a cellular system crucial for protein degradation. It involves ubiquitin, a small protein that tags proteins for degradation, and the proteasome, a complex that breaks down these tagged proteins. The process is likened to a sniper scenario, where ubiquitin enzymes (E1, E2, E3) mark proteins for destruction. The script also discusses the clinical relevance of this pathway, including its association with cancer, neurodegenerative diseases, and infectious diseases.

Takeaways

• 🔍 The ubiquitin proteasome pathway is critical for cellular homeostasis by degrading misfolded, damaged, and non-functional proteins.
• 🏷 Ubiquitin is a small protein that acts as a 'degradation tag' for proteins targeted for degradation.
• 🔪 The proteasome is a large complex that functions like a 'shredding machine', breaking down the tagged proteins.
• 🎯 The pathway involves a coordinated effort between E1, E2, and E3 enzymes to mark proteins for degradation.
• 🤝 E3 enzymes, or ubiquitin ligases, are particularly important as they facilitate the transfer of ubiquitin to the target protein.
• 🔗 Polyubiquitination is the key mark for protein degradation, unlike monoubiquitination which is a modification and not necessarily linked to degradation.
• 🧬 The proteasome consists of a 19S regulatory particle for recognition and unfolding, and a core particle that degrades the protein.
• 🔄 The process involves recognition of the polyubiquitinated protein by the proteasome cap, unfolding, and translocation to the catalytic core for degradation.
• 🏥 Clinically, the ubiquitin proteasome pathway is significant in diseases like cancer and neurodegenerative disorders such as Alzheimer's and Parkinson's.
• 🦠 In infectious diseases, some pathogens inhibit the proteasome pathway to avoid being recognized and presented by MHC molecules.

Q & A

What is the ubiquitin proteasome pathway?

The ubiquitin proteasome pathway is a cellular system responsible for protein degradation, particularly targeting misfolded, damaged, or non-functional proteins to maintain cellular homeostasis.

Why is the ubiquitin proteasome pathway important for cells?

It is crucial for maintaining cellular homeostasis by ensuring the degradation of misfolded, damaged, or non-functional proteins, thus functioning as a quality control mechanism.

What is the role of ubiquitin in the pathway?

Ubiquitin is a small protein that tags proteins for degradation, acting as a 'degradation tag' for the proteasome to recognize and degrade.

How does the proteasome function in the pathway?

The proteasome is a large proteolytic complex that degrades proteins marked by ubiquitin, functioning like a 'shredding machine' for proteins.

What are the two main components of the ubiquitin proteasome pathway?

The two main components are ubiquitin, which tags proteins for degradation, and the proteasome, which degrades the tagged proteins.

What are the different enzymes involved in the ubiquitination process?

The enzymes involved are E1 (ubiquitin-activating enzyme), E2 (ubiquitin-conjugation enzyme), and E3 (ubiquitin ligase), which work together to tag proteins for degradation.

How does the E3 enzyme contribute to the ubiquitination process?

E3 facilitates the transfer of ubiquitin from E2 to the lysine residues of the target protein, effectively flagging it for destruction by the proteasome.

What is the difference between polyubiquitination and monoubiquitination?

Polyubiquitination is a tag for protein degradation, where the protein is marked for several rounds of ubiquitination. Monoubiquitination, on the other hand, is a protein modification that does not necessarily lead to degradation.

What are the components of the proteasome and their functions?

The proteasome consists of a 19S regulatory particle for recognition and unfolding of ubiquitinated proteins, and a core particle that contains the catalytic unit responsible for degrading the protein.

How does the proteasome recognize and degrade proteins?

The proteasome recognizes polyubiquitinated proteins, unfolds them using the 19S regulatory particle, and then degrades them into small peptide fragments in the catalytic core.

What are the clinical implications of the ubiquitin proteasome pathway?

Dysregulation of the ubiquitin proteasome pathway is associated with diseases such as cancer, neurodegenerative diseases like Alzheimer's and Parkinson's, and infectious diseases where pathogens may inhibit the pathway to evade degradation.

Outlines

00:00

🛡️ Ubiquitin Proteasome Pathway: Cellular Quality Control

This paragraph introduces the ubiquitin proteasome pathway, a critical cellular system for protein degradation. It underscores the pathway's role in maintaining cellular homeostasis by degrading misfolded, damaged, and non-functional proteins. The paragraph likens ubiquitin to a 'degradation tag' and the proteasome to a 'shredding machine'. It explains the pathway's mechanism involving E1, E2, and E3 enzymes that coordinate to mark proteins for degradation. The video uses a sniper analogy to illustrate how the proteasome selectively degrades proteins marked by ubiquitin, highlighting the importance of polyubiquitination as the key mark for degradation.

05:01

🔬 Detailed Mechanism of the Ubiquitin Proteasome Pathway

The second paragraph delves into the step-by-step process of the ubiquitin proteasome pathway. It describes the activation of ubiquitin by E1 enzyme, the transfer of ubiquitin to target proteins by E2 and E3 enzymes, and the recognition of polyubiquitinated proteins by the proteasome. The paragraph further explains the proteasome's structure, including the 19S regulatory particle and the catalytic core, which unfolds and degrades the protein. The video provides a visual analogy of the proteasome's operation, comparing it to a shredding machine that processes proteins. It also touches on the clinical relevance of the pathway, mentioning its association with diseases such as cancer and neurodegenerative disorders like Alzheimer's and Parkinson's.

Keywords

💡Ubiquitin

Ubiquitin is a small protein composed of 76 amino acids that plays a critical role in tagging proteins for degradation within the cell. It is likened to a 'degradation tag' in the script, which is essential for maintaining cellular homeostasis by marking misfolded, damaged, or non-functional proteins for destruction. The process of tagging involves a series of enzymes, E1, E2, and E3, which work together to polyubiquitinate the target protein, flagging it for degradation by the proteasome.

💡Proteasome

The proteasome is described as a large proteolytic complex that acts like a 'shredding machine' in the cell. Its function is to degrade proteins that have been marked by ubiquitin for destruction. The video script uses the analogy of a sniper to explain how the proteasome specifically targets proteins tagged with polyubiquitination for degradation, ensuring that only the proteins designated for destruction are affected.

💡Protein Degradation

Protein degradation is a vital cellular process that involves breaking down proteins that are misfolded, damaged, or no longer needed. In the context of the video, the ubiquitin-proteasome pathway is the primary system for this degradation. It is essential for cellular quality control and maintaining homeostasis by removing non-functional proteins.

💡Cellular Homeostasis

Cellular homeostasis refers to the stable internal environment of a cell, which is crucial for its proper functioning. The ubiquitin-proteasome pathway contributes to this stability by ensuring that only the correct proteins are present in the cell at any given time. By degrading misfolded or damaged proteins, the cell maintains its balance and prevents the accumulation of harmful or non-functional proteins.

💡Polyubiquitination

Polyubiquitination is the process of attaching multiple ubiquitin molecules to a target protein, which is a signal for the proteasome to degrade that protein. The video script explains that this process is facilitated by E3 enzymes, which coordinate with E2 enzymes to transfer ubiquitin to the target protein. This tagging is a key step in the degradation pathway, as it marks proteins for destruction.

💡E1 Enzyme

The E1 enzyme, also known as the ubiquitin-activating enzyme, is the first in the series of enzymes involved in the ubiquitin-proteasome pathway. It activates ubiquitin in an ATP-dependent manner, preparing it to be transferred to the target protein. This activation is a critical first step in the process of protein degradation.

💡E2 Enzyme

The E2 enzyme, or ubiquitin-conjugation enzyme, plays a central role in transferring activated ubiquitin from the E1 enzyme to the target protein. It works in conjunction with E3 enzymes to ensure that ubiquitin is correctly attached to the lysine residues of the protein, marking it for degradation.

💡E3 Enzyme

The E3 enzyme, or ubiquitin ligase, is responsible for recognizing the target protein and facilitating the transfer of ubiquitin from the E2 enzyme to the protein. It ensures that the correct proteins are tagged for degradation, acting as a specificity factor in the ubiquitin-proteasome pathway.

💡Lysine

Lysine is an amino acid residue that is targeted for ubiquitination during the protein degradation process. The video script mentions that after polyubiquitination, which involves the attachment of ubiquitin to several lysine residues, the proteasome recognizes this tag and degrades the protein. Lysine plays a crucial role in the marking process for protein degradation.

💡19S Regulatory Particle

The 19S regulatory particle is a component of the proteasome that recognizes ubiquitinated proteins, unfolds them, and sends them to the core of the proteasome for degradation. As described in the script, this particle is part of the proteasome's mechanism for identifying and processing proteins marked for destruction.

💡Unfoldase Ring

The unfoldase ring is a part of the proteasome's structure that unfolds the target protein from its native structure, preparing it for degradation. The script uses the analogy of a shredding machine to describe how the unfoldase ring threads the protein through to the catalytic core, where it is degraded into small peptide fragments.

Highlights

The ubiquitin proteasome pathway is critical for cellular protein degradation.

This pathway maintains cellular homeostasis by degrading misfolded, damaged, and non-functional proteins.

Ubiquitin is a small protein that tags proteins for degradation, acting as a 'degradation tag'.

The proteasome is a large complex that degrades ubiquitinated proteins, likened to a 'shredding machine'.

The pathway is compared to a sniper scenario, where ubiquitin tags help the proteasome identify target proteins for degradation.

Ubiquitin is activated by the E1 enzyme in an ATP-dependent manner.

The E2 enzyme, or ubiquitin conjugation enzyme, transfers ubiquitin to target proteins with the help of E3.

E3 enzymes coordinate with target proteins and facilitate the transfer of ubiquitin from E2, flagging them for destruction.

Polyubiquitination is the key mark for proteasome-mediated degradation.

Polyubiquitinated proteins are destined for degradation, unlike monoubiquitinated proteins which may not be degraded.

The proteasome consists of a 19S regulatory particle and a core particle, which contains the catalytic unit for protein degradation.

The proteasome recognizes polyubiquitinated proteins, unfolds them, and degrades them in an ATP-dependent process.

The clinical relevance of the ubiquitin proteasome pathway includes its association with cancer and neurodegenerative diseases.

Dysregulation of the UPS pathway is implicated in cancer development.

Neurodegenerative diseases like Alzheimer's and Parkinson's are linked to impairments in the ubiquitin proteasome machinery.

Pathogens can inhibit the proteasome pathway to evade immune system recognition.

The video provides educational content on the ubiquitin proteasome pathway with practical applications and clinical significance.

Transcripts

in this short video we'll talk about

ubiquitine proteasome protein

degradation pathway so ubiquitine

proteasome pathway is a system which is

very critical for the cell which

regulates protein

degradation question is what is the

utility of this pathway for a cell why

it is important for the cell because

this kind of pathway ensures that it

degrades misfolded damaged and basically

non-functional proteins to maintain

cellular homeostasis so one can imagine

this to be a quality control pathway as

well so there are two main components to

it one is ubiquitine which is a small

protein 76 amino acid long and that tags

the protein for degradation so it's kind

of like a degradation tag and then there

is a proteosome which is a large

proteolytic complex that degrades the

uated proteins which were previously

marked for degradation so it's kind of

like a shredding machine

now this kind of pathway is pretty

similar to this real life scenario

imagine this particular sniper has to

kill one particular uh person in a crowd

but how does the sniper recognize who is

the target person until and unless

somebody tags that person it's

impossible for the sniper to look at

that and here the person may be a spy

who pointed out this is the person to

kill and then the sniper can kill

similarly the proteosome is the sniper

proteosome doesn't know which particular

protein to degrade proteosome doesn't

know whether that protein is

nonfunctional aggregated or misfolded so

proteomes job is just like a sniper to

kill or to degrade and the main job is

done by the

polyubiquitinated tag which is provided

by these ubiquitin uh uh enzymes

basically there are E1 E2 and E3 enzymes

which in coordination flag the

particular protein with poly

ubiqutination Mark and that's the key

mark for degradation by

proteosome so let us talk about the

step-by-step process of ubiquitine

proteosome pathway so first of all the

E1 enzyme which is ubiquitine activating

enzyme activates the ubiquitine in an

ATP dependent manner then there is E2

protein which kind of is a conjugation

enzyme so it's known as ubiquitine

conjugation enzyme it transfers the

ubiquitine residues to a Target protein

and it does that with the help of e3 so

E3 kind of coordinates with the target

protein and E2 transfer the ubiquitine

protein into the target protein kind of

flagging them for Destruction so E3 is

the ubiqutin liase and it facilitates

the transfer of ubiqutin from the E2 to

the lysin residues of the target protein

always remember that lysin is the

residue that gets

ubiquitinated after poly ubiqutination

that means ubiqutination for several

times proteasome recognize this poly

ubiqutination tag and degrades the

protein just like a shredding machine so

in some word proteosome is kind of like

a molecular shredding

machine it's important to note that

polyubiquitinated proteins are destined

to be degraded so poly ubiqutination tag

is a tag that is interpreted for

degradation but mono ubiquit inated

proteins might not be degraded it's

basically a kind of like a protein

modification that can happen so it

doesn't require to be degraded but a

poly ubiquity ination tag would be now

let's talk about the proteosome a little

bit more so proteosome has different

component it has a 19s regulatory

particle which recognize ubiquitinated

protein unfolds them and eventually send

it to the core now the core which is

marked here in the red is the main

particle it has the catalytic unit which

literally uh degrades the protein and

chops off the protein like a shredding

machine so there are two things that are

happening one is recognition another is

destruction of the protein so here is a

kind of like cross-section view of the

proteosome where we can zoom and see the

head of the proteosome has the cap which

recognize the particular ubiquitylated

poly uated protein and channel those

proteins and unfold that protein through

sprad it through the catalytic core so

now we are going to look at that process

in detail so here is the cap here is the

unfold as ring so unfold as Ring's job

is to unfold the protein from its native

structure there is a central cylinder

which has the catalytic core shown in

yellow now here is a protein that gets

recognized by the cap using the

uated uh poly uated residue now notice

how the protein is threaded through the

unfold as ring to the catalytic core so

the unfold as ring literally rips off

the the protein into its primary

structure and pass it through this

narrow ring eventually what happens is

the catalytic core starts degrading the

protein and chops off into small peptide

fragments this is how proteosome works

so overall there are two things the

proteosome cap recognize the poly uated

protein and the translocation of the

protein happens to the catalytic core

which degrades the protein in an ATP

dependent manner so clinically utin

proteosome path is important for cancer

disregulation of UPS pathway or utin

proteosome pathway has been shown to uh

be associated with cancer it is

associated with uh neurod degeneration

for example Alzheimer's disease

Parkinson disease has impairment in

ubiqutin proteosome Machinery which pre

which leads to protein aggregation

because this is kind of like a quality

control

mechanism then there is in involvement

of these pathway in infectious disease

some of the pathogens literally inhibit

the proteosome pathway to prevent uh

things to be degraded so basically if

immunoproteasome doesn't degrade them

then it is never been recognized or

never be displayed on the class one MHC

molecule so that is why uh many

infectious pathogens suppress the

proteosome pathway so I hope this video

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