Secretory Pathway: UPR, The Golgi and Lysosomes - Vocabulary Flashcards

Purpose: The cell's plan to relieve stress in the ER (Endoplasmic Reticulum) caused by too many proteins being unfolded or misfolded.
Trigger: Many proteins in the ER are not folded correctly.
Cell's Actions during UPR:
- Make more chaperones (helper proteins) to help proteins fold right.
- Make more proteases (destroyer proteins) to get rid of bad proteins.
- Slow down making new proteins to give the ER a break.
How it starts: Special sensors in the ER know when bad proteins build up. They tell the cell to start the UPR.
Why it matters (Disease): If the UPR fails, misfolded proteins can cause diseases like Cystic Fibrosis (CF). In CF, a protein called CFTR is misfolded and destroyed instead of working.

Goal: Make sure N-linked glycoproteins (proteins with sugar chains) fold correctly in the ER.
How it works (simplified steps):
- The protein gets some sugars removed.
- If it's not folded right, Calnexin (an ER helper) grabs it, and a protein called UGGT adds a sugar back. This sends the protein back to try folding again.
- If it is folded right, the last sugar is removed, and the protein leaves the Calnexin cycle.
Outcome: Only correctly folded proteins can move further in the cell; bad ones stay and get removed.

Idea: Changes (mutations) in genes can make proteins that don't fold right.
Result: The cell's quality control system catches these bad proteins and gets rid of them, causing the cell to lose important functions.
Importance: Shows how vital proper protein folding is for health and how fixing folding might help treat diseases.

Question: How do proteins leave the ER and get to the Golgi?
COPII Vesicles (Forward Transport): Small sacs (vesicles) with a protein coat that carry cargo from the ER to the Golgi.
- How the coat forms and picks cargo:
  - Sar1: A small switch-like protein. It's turned on by a helper protein (GEF) in the ER membrane, changing from ext{Sar1-GDP} to ext{Sar1-GTP}. This makes it stick to the membrane and start bending it.
  - Sec23/24: Inner coat proteins that help pick the right cargo and bend the membrane.
  - Sec13/31: Outer coat proteins that complete the vesicle's outer shell.
- Steps to make a COPII vesicle:
  1. A helper in the ER wall activates Sar1. ext{Sar1-GDP} \rightarrow ext{Sar1-GTP}. This makes Sar1 stick to the ER wall.
  2. Active Sar1 brings in Sec23/24, which start forming the coat and grab cargo.
  3. Sec13/31 join to finish the coat, and the vesicle pinches off.
  4. Sar1 becomes inactive (GTP changes to GDP), the coat falls off, and the COPII vesicle is ready to fuse with the Golgi.
- Cargo Selection: Special cargo receptors in the membrane help pack the right proteins into the vesicle.

After budding: Vesicles need to go to the correct place (e.g., ER to Golgi).
Three main protein families for directing vesicles:
- Rab GTPases: Small switch proteins that guide vesicles to the right membrane.
- Tethering proteins: Long proteins that act like ropes, catching vesicles at the target membrane.
- SNARE proteins: Proteins that make membranes stick together and fuse:
  - v-SNAREs: On the vesicle.
  - t-SNAREs: On the target membrane.
  - They zip together to pull the membranes close for fusion.
Rab-Tethering connection: Active Rab on the vesicle works with tethering proteins on the target membrane to hold the vesicle in place.
SNAREs and Fusion: v-SNAREs and t-SNAREs tightly link up, pulling the vesicle and target membranes until they merge. This mixes their contents.
After fusion: SNAREs need to be taken apart to be reused. Another protein called NSF (using ATP energy) pulls them apart.

Vesicle Pinching: Driven by dynamin, a protein that forms a ring around the neck of the budding vesicle.
How it pinches: When dynamin uses energy (GTP changes to GDP), it squeezes and cuts the vesicle off from the membrane. ext{GTP} \rightarrow ext{GDP} + P_i
Coat-recruitment GTPases: Proteins like Sar1 start the formation of coats and help gather cargo for different types of vesicles.

We still don't completely understand how COPII vesicles know exactly what cargo to take from the ER or how they always find the Golgi.
Big questions: 1) How do vesicles form and find cargo? 2) How do they target the right place?

Targeting involves:
- Rab proteins: On the vesicle, they find the right organelle and bring in tethering proteins.
- SNAREs: Proteins that cause the vesicle and target membrane to fuse.
Steps of Targeting:
- Tethering: Rab proteins help tethering proteins catch the vesicle.
- Docking: SNAREs on the vesicle (v-SNARE) and target membrane (t-SNARE) link up.
- Fusion: The SNAREs pull the membranes together until they become one.

Location and Look: Near the cell's control center (nucleus), made of flattened sacs called cisternae, stacked together.
Organization: Has different parts (cis, medial, trans) that do different jobs.
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