The Endomembrane System 1

MOLECULARR DIIE

Endomembrane system

A network of membrane enclosed organelles including ER Golgi endosomes lysosomes peroxisomes and vesicles involved in protein and lipid trafficking

Invagination model

Theory that endomembrane compartments evolved from the plasma membrane folding inward explaining continuity between nuclear envelope and ER

Rough ER

Region of ER covered in ribosomes where all endomembrane proteins first enter and undergo folding glycosylation and quality control

Smooth ER

Region of ER without ribosomes involved in lipid synthesis detoxification and specialized functions

ER lumen

Interior space of the ER where soluble proteins fold form disulfide bonds and receive N linked glycosylation

Cotranslational translocation

Process where a polypeptide is threaded into the ER while translation is still happening

ER signal sequence

Hydrophobic N terminal sequence that recruits SRP and directs ribosome to the rough ER

Signal Recognition Particle SRP

Ribonucleoprotein that binds the ER signal sequence pauses translation and brings the ribosome to the ER

SRP receptor

Membrane receptor that binds SRP and positions the ribosome on the translocon requiring GTP hydrolysis

Translocon

Protein channel in the ER membrane that allows polypeptides to enter the ER lumen or embed in the membrane

Signal peptidase

Enzyme that cleaves the ER signal sequence releasing soluble proteins into the lumen

Soluble proteins

Proteins fully translocated into the ER lumen and remain within luminal spaces of endomembrane organelles or are secreted

Membrane proteins

Proteins that remain partially embedded in membranes as they travel through endomembrane compartments

Stop transfer signal

Hydrophobic sequence that halts translocation and creates a membrane spanning domain

Start transfer signal

Hydrophobic sequence used for multipass proteins to initiate insertion at later points in translation

Single pass membrane protein

Membrane protein with one transmembrane domain and defined N and C terminal topology

Multipass membrane protein

Membrane protein containing multiple start and stop signals producing several transmembrane domains

Disulfide bond formation

Covalent bonding between cysteine sulfur atoms to stabilize protein structure in oxidative environments

Protein disulfide isomerase PDI

Enzyme in the ER lumen that catalyzes disulfide bond formation

Glycosylation

Addition of oligosaccharides to proteins to protect them and aid folding stability and recognition

N linked glycosylation

Attachment of a 14 sugar oligosaccharide to the nitrogen on asparagine in an Asn X Ser Thr motif

Dolichol

Lipid anchor in the ER membrane on which the first oligosaccharide is built before transfer

Oligosaccharyl transferase

Enzyme that transfers the 14 sugar oligosaccharide to the protein during translation

Glycoprotein

Protein with covalently attached carbohydrates added in the ER and modified in the Golgi

Glycocalyx

Protective carbohydrate layer on the extracellular side of the plasma membrane

Asymmetrical membranes

Concept that membrane proteins and sugars maintain fixed orientation from ER to final destination

ER exit sites ERES

Specialized rough ER regions where properly folded proteins are packaged into vesicles

BiP

ER chaperone that binds exposed hydrophobic regions to retain misfolded proteins

Calnexin

ER chaperone that binds glycoproteins during folding quality control

ER quality control

Multi step system ensuring only properly folded and modified proteins leave the ER

Retrograde transport

Movement of vesicles backward from Golgi to ER recycling resident ER proteins and retrieving mistakes

KDEL sequence

C terminal ER retention signal that retrieves escaped ER resident proteins via Golgi receptors

Unfolded protein response UPR

Stress response activated when misfolded proteins accumulate leading to increased chaperone production and ER expansion

Ire1

ER membrane sensor that dimerizes when BiP is unavailable triggering UPR signaling

Dislocation

Export of persistently misfolded ER proteins to the cytosol for ubiquitin tagging and proteasome degradation

Transport vesicle

Membrane sphere used to move proteins between endomembrane compartments

Cargo protein

Protein specifically selected for transport in a vesicle

Coat proteins

Proteins that polymerize around vesicles shaping them and selecting cargo

COPII

Coat protein used for ER to Golgi anterograde transport

COPI

Coat protein used for Golgi to ER retrograde transport

Clathrin

Coat protein used for endocytosis and Golgi to endosome trafficking

Vesicle budding

Formation of vesicles driven by coat protein assembly on donor membranes

GEF

Guanine exchange factor that activates monomeric GTPases by exchanging GDP for GTP

GAP

GTPase activating protein that inactivates GTPases by stimulating GTP hydrolysis

Sar1

Small GTPase that initiates COPII coat recruitment at the ER

ARF1

Small GTPase used for COPI and clathrin coat recruitment

Vesicle uncoating

Removal of coat proteins triggered by GTP hydrolysis of Sar1 or ARF1

Rab proteins

Monomeric GTPases on vesicles that mediate targeting through tether and docking interactions

Tethering proteins

Long flexible proteins on target membranes that grab Rab GTP on vesicles

Docking

Step when Rab GTP binds tether positioning the vesicle close to the target membrane

SNARE proteins

Fusion machinery consisting of v SNAREs on vesicles and t SNAREs on target membranes

v SNARE

SNARE located on vesicles that pairs with t SNAREs for fusion

t SNARE

SNARE located on target membranes that coils with v SNAREs to drive membrane fusion

NSF SNAP

ATP dependent complex that separates SNARE complexes after fusion to reset them

Fusion

Step where v SNAREs and t SNAREs twist together forcing membranes to merge and deliver cargo

Anterograde transport

Forward movement ER to Golgi to plasma membrane or lysosomes

Endocytic pathway

Pathway bringing plasma membrane cargo and extracellular material into endosomes and lysosomes

Secretory pathway

Broad pathway from ER to Golgi to plasma membrane extracellular space or other organelles

Resident ER proteins

Proteins that stay in ER such as BiP PDI calnexin and oligosaccharyl transferase and are retrieved by KDEL

Resident Golgi proteins

Proteins that function and stay in the Golgi for modification and sorting

Quality control checkpoint 1

BiP and calnexin retain misfolded proteins in the ER

Quality control checkpoint 2

Misfolded proteins and escaped ER residents are returned from Golgi via COPI vesicles

Quality control checkpoint 3

UPR triggered when misfolded proteins exceed capacity of chaperones

Quality control checkpoint 4

Dislocation exporting misfolded proteins into cytosol for degradation

Quality control checkpoint 5

Apoptosis if ER stress is unresolved

Endomembrane vs cytosolic environment

Endomembrane lumen is oxidative and carbohydrate rich while cytosol is reducing and unglycosylated