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169 Cards in this Set

  • Front
  • Back
What is the most prominent substructure of the nucleus?
Is the nucleoli membrane bound?
What factors determine nuclear size?
relative size of nucleus w/n cell varies with cell fxn
Explain the nuclear membrane.
2 bilayered membranes, perinuclear space, and pores
What is found in the nucleoplasm?
lamina, matrix, and nuclear particles
What happens w/n the nucleolus?
rRNA synthesis, regulatory cell cycle proteins
What is the outer nuclear membrane attached to?
What is the outer nuclear membrane surround by?
intermediate filaments, ribosomes
What is the inner nuclear membrane stiffened by?
lamin intermediate filaments
What is the perinuclear space continuous with?
Nuclear pore complexes (NPC) fxn in what?
nuclear transport
What diffuses passively and rapidly through NPC?
small molecules, ions
retroviruses, steriods
What requires energy to be transported through the NPC?
macromolecules, proteins, snRNP's, mRNA, RNP's
Explain the NPC.
glycoproteins make up the NPC
contain centeral plug
nuclear basket that opens and closes in response to Ca
How is the NPC tethered to the membrane?
via another protein (gp210)
What is present on imported cargo proteins?
nuclear localization signals (NLS) rich in Lys and Arg
"zip codes" which tell them to enter
What does cargo entering the nucleus bind to?
alpha and beta importin
What does importin interact with while importing cargo into the nucleus?
interacts with nucleoporins and requires ATP
When importin+cargo enter nucleus, what does importin interact with?
importin beta interacts with Ran-GTP dissociating the cargo complex
What is the fxn of RanGAP?
turns OFF Ran-GTP by stimulating GTP hydrolysis
When the importin-RanGTP complex is transported back to the cytoplasm, what happens?
RanGAP hydrolyzes GTP, and Ran dissosiates from importin and the cycle starts again
When RanGDP enters the nucleus what does it interact with?
GEF:ON (nucleotide exchange factor)
Ran releases GDP, bind GTP, reactivatin Ran
What is Ran?
SMALL G-protein (only 1 subunit, not heterotrimeric)
Where is GEF found?
in nucleus
What 2 things does Ran-GTP do?
1. Helps break up importin-cargo complex, importin-RanGTP returns to cytoplasm
2. Binds exportin-cargo and helps transport to cytoplasm
Where is GAP found?
in cytoplasm
what 2 things does Ran-GDP do?
1. Breaks up Ran-cargo-exportin, Ran-GDP and exportin (not complexed) return to nucleus
2. Breaks up importin-Ran complex. Ran-GDP returns to nucleus
Cargo proteins destined for export are identified how?
leucine-rich nuclear export signal (NES), binds exportin
Once the cargo is bound to exportin, what does exportin bind to?
Ran-GTP, moves out of nucleus via interaction w/ nucleoporin
Once in the cytoplasm, how does exported cargo detach?
GAP stimulates GTP hydrolysis and cargo is released
After the exported cargo is released, what happens to RanGDP and exportin?
they move back into the nucleus and GEF catalyzes exchange from GDP-GTP
Describe mRNA transport?
-transport from nucleus to cytoplasm is highly selective
-RNA's are transported across NPC as RNA-protein complexes-heterogenous nuclear ribonucleoproteins
What are hnRNPs?
hetergenous nuclear ribonucleoproteins- form in which RNA is transported across NPC
What mRNA is transported through NPC?
mature mRNA (5'cap, poly A tail, correctly spliced)
ONLY mature allowed through
Explain mRNA export from the nucleus.
The 5 end of the fully processed mRNA hnRNP protein complex (mRNP) associates with cap-binding complex (CBC), which passes through (NPC) first. Nucleusrestricted hnRNPs are removed as a mRNP is transported through the NPC; these proteins, which lack a NES, would hold the mRNA in the nucleus. NES-bearing hnRNPs, are transported through the NPC
Before entire complex is transported, where does translation of large mRNA's begin?
All proteins found in the nucleus are synthesized where?
in the cytoplasm and imported into the nucleus
How does HBV capsid get into the nucleus?
it is small enough to cross NPC directly and phosphorylation of HBV capsid makes NLS accesible to bind to nuclear transport machinery
How does Adenovirus and Herpes Simplex virus capsids enter nucleus?
they are too big so they dock at cytoplasmic side via interactions w/ importin
HSV releases DNA, enters nucleoplasm
Adenovirus traps transport machinery, dissassembles capsid, translocates DNA
What happens to nuclear transport with Huntington's disease?
huntingtin (mutated) protein accumulates in the nucleus b/c it cant be translated out
-trinucleotide repeat diease
What are lamins?
intermediate filaments localized to the nucleus that maintain cell shape and protect membranes
What do lamins interact with?
inner membrane proteins to enable nuclear growth and promote membrane breakdown in M
interact with chromatin at periphery
What do lamins do?
organize NPC: spatial separation
interact w/ heterochromatin to protect DNA from mechanical forces
essential for replication and transcription
Lamin A and C
splice variants
How do Lamins A, B and C differ in terms of genes?
1 gene makes Lamins A/c
2 genes make B
What phosphorylates Lamins?
cyclin B/cdk1
Lamin phosphorylation causes what?
lamin meshwork breakup
Lamin dephosphorylation caues what?
lamin meshwork to reform b/c Lamin B is anchored to inner membrane and forms vesicles to enable rapid assembly
Lamins A/C are released as free dimers
What is Emerin?
Emerin is a ubiquitously expressed integral membrane protein of the inner nuclear membrane that binds preferentially A-type lamins in vitro and requires lamin A for proper nuclear envelope targeting
What does Lamin B bind to?
Lamin Binding Receptor (LBR)
What is Emery-Dreifuss Muscular Dystrophy (EDMD)?
skeletal laminopathy
defect of emerin or Lamin A/c
A defect in Lamin B causes what?
death in embryo
Features of patient with EDMD?
contractures (ankles, elbows)
weakness in shoulders
joint deformities
sudden heart failure common
What is dilated cardiomyopathy?
cardiac laminophathy
What happens if there is a Lamin A/C defect?
fragile nuclear envelope
aberrant distribution of chromosomes
leakage of lamins into cytoplasm and chromatin
Lamin A defects result in what?
muscular dystrophies, lipodystrophies, and neuropathies
What is Hutchinson-Gilford Progeria Sydrome?
defect in Lamin A/C
appearance: short stature, sculptured nose, alopecia, small face, loss of subcutaneous fat
Life excpectancy of H-G Progeria syndrome?
approx 13 years: 80% deaths from MI or congestive cardiac failure (die of diseases of old age)
What do A-type Lamins bind to?
architectural proteins
chromatin proteins
gene-regulatory proteins
signaling proteins
Fxn of nuclear matrix?
organizes chromatin
facilitates transcription/repliction
Topo II most abundant (located at centromeres)
Condensins and cohesins are what?
SMC proteins (structural maintenance of chromosomes)
What do condensins do?
regulate chromosomal condensation
what do cohesins do?
regulate sister chromatid pairing
What are chromatin fibers bound to?
directly to inner membrane and to nuclear lamina at centromeres and telomeres
What are chromosomal territories?
chromosomes are tethered to territories (to nuclear lamina and inner membrane) that restrain their movement
Each chromosome occupies its own territory--no territories overlap with another
What occurs in speckles?
mRNA processing
dynapic storage spot for splicing factors
What are speckles?
irregular domains of mRNA processing machinery
What consititutes the nuclear matrix?
insoluble, thin protein fibrils
What are Cajal bodies/GEMS?
resemble each other, often paired
involved w/ recycling of snRNPs
At which stage of the cell cylce is the nucleolus detectable?
What is the fxn of the nucleolus?
rRNA and tRNA synthesis
partial assembly of ribosomes
form spliceosomes and telomerase
contains cell-cycle regulatory proteins
What does the size of the nucleolus reflect?
# of ribosomes produced
When does the nucleolus disassemble?
during Mitosis
What are the subcompartments of the nucleolus?
fibrillar centers (FCs)
Dense fibrillar components (DFCs)
Granular component (GC)
Within what subnucleolar compartment does rRNA transcription initiation occur?
within FCs or FC-DFC boundary
What happens in the DFC of the nucleolus?
pre-RNA transcripts are cleaved and modified by snoRNPs and begin assembly with ribosomal proteins
What is happening in the nucleolar organizing region (NORs)?
Each NOR contains a cluster of tandemly repeated rRNA genes that are separated from each other by nontranscribed spacer DNA. These genes are very actively transcribed by RNA polymerase I, allowing their transcription to be readily visualized by electron microscopy. In such electron micrographs, each of the tandemly arrayed rRNA genes is surrounded by densely packed growing RNA chains (branches), forming a structure that looks like a Christmas tree.
What do the terminal knobs on the christmas tree structure represent?
snoRNP that fxn in pre-rRNA processing
What do the branches of the christmas tree structure represent?
growing rRNA strands
What is 45S pre-rRNA spliced into?
18S rRNA of 40S subunit
5.8S and 28S rRNAs of 60S subunit
Where does ribosome subunit assembly occur?
What ribosomal subunits are transcribed in the nucleolus? by what?
28S, 18S and 5.8S by RNAP I
What ribosomal subunits are transcribed outside the nucleolus?
What are snoRNA's sythesized by?
What are snoRNA's encoded by?
introns of ribosomal protiens
What do snoRNA's bind?
proteins forming snoRNPs
How do snoRNA's bind to complementary regions on pre-RNA to do what?
assist in ribosome assembly
What does the presence of a prominent nucleolus indicate? where would you find prominent nucleolus?
that the cell is actively sythesizing protein
in protein-secreting cells such as those of the pancreas, plasma cells, developing blood cell precursors and CANCER cells
What are the types of signals?
Hydrophilic ligands require what types of receptors?
extracellular receptors
hydrophobic ligands/lipid-soluble require what types of receptors?
intracellular receptors
ex: steriods, NO, CO
What is the mechanism of steriod hormone action?
hydrophobic steriod hormone diffues across membrane and binds to cytosol receptor
Steroid-receptor complex translocats to the nucleus to act as a transcription factor
What is megalin?
plasma membrane bound R that mediates the internalization and activation of Vit D3-a steriod
What are 3 R types for hydrophilic ligands?
ion channel-linked R (Ach R)
G-protein linked R
enzyme linked R (insulin)
Enzymes in a transduction pathway are often called what?
How does cAMP activate PKA?
cAMP binds to regulatory subunits releasing catalytic subunits, which then act as transcription factors
Signal transduction leads to ____?
signal amplification that requires enzymes as players
How can effectors be stimulated or inhibited?
by stimulatory or inhibitory G proteins
How does down-regulation of Receptor occur?
by internalization through endocytosis
How does desensitization of R occur?
R is phosphorylated allowing ARRESTIN to attach and block interaction with G protein, thereby desensitizing R
When can Arrestin bind to a R?
when the R is phosphorylated
What is crosstalk?
convergence of multiple pathways to common points of control
involves 2 or more different systems w/ different hormones and different R's
What are the major control routes of crosstalk?
gene transcription
modulation of waiting enzymes
What are the key features of GPCR's?
7 membrane spanning alpha helical domains
phosphorylation sites for arrestin (desensitization)
site to interact w/ G protein
lipid anchor anchoring R to membrane
What happens after the G protein attaches to the R?
GDP on alpha subunit displaced with GTP
What does the alpha subunit of G protein do?
interact with effector, modulating its activity
has GTPase activity
When does the alpha subunit reassociate with G protein?
once GDP is present on the alpha it leaves effector shutting off signal
What is the fxn of the betagamma complex of G protein?
after alpha dissociates, betagamma opens the ion channels
what is the affect of activated adenylyl cyclase on cAMP?
activates cAMP by removing 2 PHOSPHATES from ATP which in turn activates PKA
What is the affect of phosphodiesterase on cAMP?
breaks down cAMP: Viagra blocks cGMP phosphodiesterases to prolong relaxation response
How can PKA act as a transcription factor?
by phosphorylating CREB (CRE Binding Protein)to allow CREB to then bind to CRE (cAMP response element) and affect transcription
What effect does cholera toxin have on signal transduction?
it locks the alpha subunit of G protein in an ACTIVE, monomeric state causing continual increase in cAMP
What effect does Pertussis (whopping cough) have on signal transduction?
it locks the alpha subunit of G protein in INACTIVE, hetertrimeric state causing increaed cystolic cAMP
How is PLC activated?
by activated G protein alpha subunit
Once activated what does PLC do?
cleaves PIP2 into IP3 and DAG
IP3 opens up ER Ca channels
Ca then activates PKC
DAG also activates PKC
Is PIP2 (phosphatidylinositol) on the inner or outer leaflet of the membrane?
inner with 2 free phosphates available
What are 2 examples of enzyme linked R's? ligands for them?
RTK, receptor tyrosine kinase
cytokine receptors
ligands: GFs, cytokines, death signals
When ligands bind to RTK receptors it induces what?
when ligands bind tyrosine R's it induces dimerization of R's
What is Ras-GTP? How activated?
signaling molecule in cytosol(proto-oncogene)
activated via Grb2 and Sos
What are Grb2 and Sos?
docking protiens that activate Ras-GTP
What happens when cytokines bind R's?
ligand binding causes dimerization of R's
JAK phosphorylates itslef and tails
JAK p-lates STAT
STAT dimerizes and enters nucleus
What activates mitogen-activated protein kinases (MAP-kinase)?
when GF's bind to GF R's activating small GTP-binding protein Ras
Ras interacts with Raf protein kinase
Raf p-lates and stimulates MAP-Kinase
How are the 2 halves of the insulin R attached?
covalently via disulfide bridges
Activation of insulin R can lead down what 2 paths?
Ras path affecting transcription
cytoplasmic vesicle fusion increasing # of GLUT transporters
When is Ca used as a 2nd messenger?
when high speed transmission is needed (nervous system and mm)
Explain excitation-contraction coupling.
DHP R on T-tubule is mechanically linked to RyR on SR
When DHP senses voltage, it opens up RyR letting Ca out into T-Tubules leading to muscle contraction
Ca can also leave SR w/ IP3 R
Which are faster: ionotropic R or metabotropic R?
ionotropic R's are fast
What turns on NO synthase?
action of NO?
diffuses to smooth muscle and turns on guanylate cylcase creating cGMP which stimulates Ca pumps to lower intracellular Ca bringing about relaxation
Where is the ERGIC located?
b/n ER and Golgi
What are the 2 ways in which proteins move through the golgi?
vesicular transport model (COP II)
cisternal maturation model (COP I)
What happens to proteins destined for lysososomes?
get a phosphate put on an exposed mannose to create mannose-6-P tage in cis Golgi
Describe the symmetry of NPCs and histones.
8 fold symmetry
Fxn of ribosomes?
RNA translation
small subunit binds first initiator tRNA
codons on mRNA bp w/ anticodons on tRNA
Once proteins are translated, what do they have that directs them to a particular location?
signal sequence
How are proteins oriented in the organelles and plasma membrane?
what starts out facing cytosol will always remain facing cytosol!
ER signal sequence targets proteins to what?
to the secretory pathway: includes secreted proteins
plasma membrane proteins, and endosomal proteins
Explain how ribosomes are directed to ER to form rER.
If a protein has an ER signal sequence, the signal sequence is bound by SRP. SRP then binds to its receptor on ER membrane. This complex brings the ribosome to a translocon which binds the ribosomes to the ER.
What happens to soluble/secreted protins that have an ER signal sequence?
the signal sequence binds t othe translocon channel interior and the growing chain hops into the channel and traverses the bilayer. Signal peptidase cleaves off the signal sequence allowing protein to enter ER lumen
explain how intergral membrane ER proteins are made.
translocating protein begins folding into alpha helical structure in the pore, creating stop-transfer signal. Remainder of the protein folds in the cytosol leaving hydrophilic domains on either side of bilayer. Hydrophobic alpha helix then causes translocon to separate, freeing the protein
What type of protein is created when the signal sequence position is past the amino end?
seven membrane spanning proteins
what chaperone proteins help protein start folding after it enters the rER?
BIP and Calnexin
What happens to misfolded proteins?
they are given a second chance and then chewed up
What type of events happen in the rER?
quality control
disulfide bond formation
What happens if a protein cannot be fixed with chaperones?
ejected back through translocon to cytosol
cystolic Ubiquitin attaches to the misfolded protein
this complex is then taken up into proteasome and degraded to amino acids
Where are proteasomes located?
in the cytosol
Where/when does glycosylation occur?
in the ER lumen as a protein is folding
explain N-glycosylation
oligosachharide is assembled on dolichol (lipid) anchor first in cytosol then flipped to ER where more sugars are added then transferred to ASPARAGINE group
Happens in rER
what type of glycosylation happens in the golgi?
O-linked when sugars are attached one at a time onto SERINE or THREONINE side groups
What does the reducing environment of the ER encourage?
cysteine-cysteine bonds and selective proteolysis
How do vesicles travel from ER to golgi?
on MT tracks
KDEL is on ___ proteins while KKXX is on ___ proteins?
KDEL: free
KKXX: membrane bound
these proteins stay behind in rER
Explain vesicle formation/budding.
cargo R's bind cargo
cargo coalesce in membrane w/ integral proteins
adaptor proteins link integrals to coatamers
coatmers allow vesicle to form ball like structure
coatamers fall off revealing SNAREs
Fxn of ARF?
small G protein that binds GTP and recruits coatamers to vesicle budding sites
Where is sialic acid added? mannose?
trans Golgi: sialic
cis Golgi: mannose
What are the 2 types of exocytosis?
regulated and constitutive
What is constitutive secretion?
continuous secretion
vesicle made then travels to cell surface and fuses
Needs to be constantly secreted
What is regulated secretion?
vesicles wait for EXTERNAL signal (hormone, NT)
NT then causes increase Ca
(histamine waiting in vesicles for signal)
What is the default secretion pathway?
What occurs as vesicle/granule matures?
undergo proteolysis (proinsulin-insulin)
condensation/concentration of contents by increase acidity and Zn
clathrin coat is removed
What is pro-insulin cleaved to?
insulin + C peptide
Explain the plasma membrane of polarized cells.
The plasma membrane of polarized epithelial cells is divided into two domains, apical and basolateral, which are separated by tight junctions and contain different species of proteins
What is the indirect protein sorting pathway? Process is called what?
protein retrieved from one membrane (basolateral) is then transported to another via early endosomes
Some polarized cells use TRANSCYTOSIS to sort membrane proteins from the basal to the apical surface
How is transcytosis used to traffic IgGs across intestinal epithelium?
the intestinal lumen has a pH of 6, while the blood has pH of 7. Fc receptors will only bind IgG in pH 6. Therefore they bind them in lumen and endocytose complex into epithelial cell. Then move across the cell, and fuse with the basal membrane, where they release the IgG (exocytosis). Unloaded receptors are recycled by transcytosis in the opposite direction: endosomes form from the basal membrane, move across the cell, and fuse with the luminal membrane
How are IgGs released into blood?
once endosome fuses with basal membrane, the pH of 7 will cause the Fc to let go of the IgG and release it into the blood
Where are GPI-anchored proteins directed?
apical membrane where they associate with glycophingolipids and cholesterol to form rafts
Rafts form specialized regions where?
in trans-golgi membrane
What carb-binding proteins stabilize rafts?
important for segregation/sorting
What do membrane proteins destined for basolateral membrane have what?
sorting signals in their cytoplasmic tail: conserved Tyr and adjacent Leu