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Flashcards in MCP 1-12 Deck (18):

Functions of the Endoplasmic Reticulum (ER)

- Protein synthesis/import (RER)
- Protein modification (RER)
- Protein quality control (RER)
- Lipid synthesis (SER)
- Synthesis of steroid hormones (SER)
- Detoxification of lipid soluble drugs (SER)
- Calcium storage (SER)


Destinations of proteins made in ER

- lumens or membrane of ER, Golgi, lysosomes, or endosomes
- plasma membrane
- cell exterior
* Once in ER, ind. proteins do not return to cytosol - stay in ER or move to other organelles via vesicles (requires sorting signals)
Note - proteins made in cytosol can remain in cytosal


Protein import into ER

- occurs co-translationally (only place this occurs)
- All protein synthesis begins in cytosol -> ER target signal directs ribosome to ER membrane -> synthesis continues w/ new poly. entering ER membrane or lumen
- No ER targeting sign = stays in cytosol


Role of SRP and SRP Receptor

- SRP (signal-recognition particle): binds ER signal sequence as it emerges from ribo, slowing protein synthesis
- Ribo/SRP complex binds ER membrane, with SRP binding SRP receptor and ribosome binding the translocation channel
- SRP binding receptor -> SRP releases signal sequence -> synthesis resumes with protein threaded thru translocation channel
- SRP recycled to cytosol


Import of soluble proteins into ER lumen

- ribo/SRP complex binds, N terminal signal sequence opens translocation channel, protein threaded through loop
- Signal peptidase cleaves off signal sequence (in lumen), protein is free and signal peptide is degraded
- ex. ER resident proteins (BiP), lyososomal proteins (nucleases), secreted proteins (insulin, growth factors)


Import of membrane proteins into ER membrane

- signal sequence of these proteins located on N terminal (cleaved) or internally
- membrane spanning domains are released laterally from the translocation channel, embedded in ER membrane
- inserted in only one orientation (topology) as dictated by signal sequence


Protein modifications in ER

- signal sequence cleavage (co-translational), by signal peptidase
- N-linked glyosylation (co-translational): imported proteins converted to glycoproteins (add sugars)
- hydroxylation of collagen: allows interchain H bonds to stabilize collagen
- protein folding and disulfide bond formation (help of chaperone proteins)
- assembly of multi-subunit proteins
- retention of ER resident proteins - retention sequence that is different than ER targeting signal (pass thru and retained)


Protein Quality Control in ER

- exit from ER is highly selective
- Proteins folded/assembled incorrectly are kept in ER by binding to chaperone proteins
- Mistake is held until corrected or will be degraded via proteasomes
- ER controls quality of proteins shipped off to other organelles


Unfolded Protein Response (UPR)

- Triggered when ER is overwhelmed by misfolded proteins (accumulate)
- UPR signals ER to expand and increase chaperones to handle unfolded proteins
- Load still too large -> apoptosis


Membrane lipid synthesis in ER

Newly synthesized phospholipids are added to cytostolic side of ER membrane, redistributed by enzymes that transfer around bilayer (scramblases, flippases)


Synthesis of Steroid Hormones

- smooth ER
- more smooth ER is present in cells that syn. hormones
- ex. Leydig cells (secrete testosterone) in testes have a lot of SER for testosterone synthesis


Detoxification of lipid soluble drugs

- function of the SER
- Liver cells have more SER for lipid metabolism. Also detox lipid soluble drugs/alcohol


Calcium storage in ER

- release of calcium mediates intracellular signaling
- ER has high concentration of calcium (1-3mM)
- in muscle, sarcoplasmic reticulum releases calcium in response to AP to induce muscle contraction


Vesicular transport: pathways

1. Secretory pathway: outward transport, proteins syn. in ER are delivered to cell surface or lysosomes via Golgi
2. Endocytic pathway: inward transport, extracellular molecules taken up by PM and delivered to lysosomes (via endosomes) for degradation


Assembly of clathrin coat

- protein coats have signal molecules to direct vesicle
- clathrin (major coat protein) forms a basketlike network consisting of hexagons and pentagons
- thought to drive budding by inducing curvature
- adaptins (2nd major coat protein): bind clathrin coat to vesicle membrane; interacts with clathrin and cargo receptors to select cargo molecules for transport


Structure of clathrin

- 3 heavy chains
- 3 light chains
- Form 3 legged structure --> soccer ball structure



- small monomeric GTP-binding protein
- assembles as ring around bud
- hydrolysis of GTP -> ring constricts -> vesicle pinches off
- clathrin coat quickly removed for disassembly once pinched


Surface markers on vesicle surface

1. Rabs: monomeric GTPases, markers that identify membrane type, recognized by tethering proteins on target membranes
2. Tethering proteins: capture vesicles via interaction with Rabs
3. SNAREs (v on vesicles, t on target membrane): determine if vesicle brought in by tethering protein is the right match -> dock or release
- Fusion of vesicle requires energy (water must be displaced), catalyzed by SNAREs - wrap around each other and pull memranes close enough to fuse