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Cell Signalling and Neurochemistry > New Deck > Flashcards

New Deck Flashcards

1
Q

how can specificity be obtained ubiquitination of proteins? I.e. for different functions (trafficking, endocytosis etc..)

A
  • different E3, E2 ligases –> different Ub linkages –> different functions
    *
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2
Q

how is organised aggregation and macro-autophagy used to reduced misfolded proteins?

A

macro-autophagy

  • engulfment of large aggregates into autophagosomes
  • may be last resote to destroy the protein

organised aggregation (inclusions)

  • shunting small aggregates into one location may decrease wider damage to cell cytosol
  • neurons less likely to die if form inclusions
  • protective effect if inclusive
  • inclusions may be degraded by autophagy
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3
Q

how is the substrate specificity controlled in cyclin.CDK?

and

how is substrate specificity controlled by diff cyclin/CDK?

A
  • cyclin/CDKs are Ser/Thr proline-directed kiases
  • phosphorylated Ser/Thr followed by proline is obligatory
  • a Lys or Arg is preferred in +3 position
    • Thr Pro X Arg
  • cyclins regulate CDK sunstrate specificity to control progression through different cell cycle stages

diff cyclin.CDKs

  • depending on which cyclin binds CDK, this det the kinetics of phosphorylation
    • i.e. diff residues phosphor
  • some cyclins binds specific recognition sequences in sub’s
  • differential sub cellular distributions
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4
Q

how do chaperons respond to aggregating proteins?

A
  • up-regulated to cope with additional stress on proteostasis
  • suppress misfolding pathways
  • try to prevent misfolded protein aggregating
    • they deepen/degrade folding pathways
  • they direct them to proteosome if cannot be refolded
  • may also direct them to autophagic degradation if others fail
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5
Q

what are the 3 delivery mechanisms to the lysosome?

A
  1. macroautophagy - use of membrane that seals to form double membrane vesicle, which is delivered to lysosome
  2. microautophagy - cargo delivered directly –> lysosome
  3. chaperon-mediated autophagy (CMA) - cargo is selectively recognised by cytosolic chaperon that mediates delivery
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6
Q

what effect does hyper/hypo thyroidism have on basal metabolic rate?

A

hyper- increased BMR (weight loss, increased food req, heat intolerance)

hypo - decreased BMR

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7
Q

how can HSP70 influence huntingtin polyQ aggregation in cells?

A
  • long polyQ (Q78) –> aggregation
  • HSP70 colonises with the long polyQ
  • overexpression –> neuroprotection
  • BUT mutant HSP70 enhances polyQ toxicity as they have less capcity to deal with misfolding
  • does NOT stop disease
    • chaperons sucked out by co-aggregation
    • protein quality control de-stabilised by misfolded proteins
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8
Q

describe how CytC initiates death cascades in the cytosol.

A
  • proteins e.g. Bax contribute to formation of pore in outer mitochondia mem
    • released through mem mediated by some proteins
    • Bcl2 family member
  • CytC forms complex with Apaf-1 (apoptotic protease activating factor-1) that activates caspase 9 then caspase 3 (apop protease)
    • allows death cascasde to occur
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9
Q

describe the homeostatic control of TH secretion.

A
  • paraventricular nucleus secretes TRH (thyroid releasing hormone)
  • TRG –> anterior pituitary and stimulates release of TSH
  • TSH stimulates thyroid to produce hormones (T3 and T4)
  • T4 and T3 - negative feedback on TRH and TSH
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10
Q

how can GF influence cell death?

A
  • in absence of GFR activation >> cell death
  • Bad stop’s Bcl2’s protective actions in mitochondrial outer membrane
  • caspase cleaves proteins >> death
  • GF can antagonise these apoptotic signalling events at multiple points
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11
Q

what are some stratergies for targeting Bcl2 and Bclx?

A

to change levels of these anti-apoptotic proteins

to hcnage activity of anti-apoptotic proteins

screen for inhibitors

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12
Q

describe TNF activation of apoptosis or necroptosis.

A
  1. tumour necrosis factor (TNF) binds R
  2. complex 1 forms which activates signal transduction pathways that lead to activation of NFKB
    1. NFKB targets gene that response to necrosis factor
  3. Poly Ub on complex 1 then forms complex 2
  4. caspase can change activity –> apoptosis, if caspase does not bind —> necroptosis
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13
Q

describe the initiation of macroautophagy.

A

initiation at phagophore assembly site (PAS)

  1. will ultimately grow and fuse to form dbl membrane
  2. proteins reg formation
  3. essential proteins are called the CORE MOLECULAR MACHINERY - provides mechanisms for control
    1. Atg/unc51-like kinase complex
    2. ubiquitin-like protein complex system
    3. class III PI3K/Vps34 complex
  4. formation of PAS from plasma mem requires components of endocytic machinery
  5. inhibiting Clathrin-mediated endocytosis or distruption of Atg16L interaction with components of clathrin-dep endocytosis –> inhibition of formation of autophagosome
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14
Q

describe the extrinsic apoptotic pathway.

A
  1. recruitment of adaptors to death domains e.g. Fadd (Fas adaptor protein bidnng death domain)
  2. adaptors lead to activation of caspase 8 (not in intrinsic pathway)
  3. caspase 8 then activates caspase 3
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15
Q

how is misfolding protein implicated huntington’s disease?

A
  • cause of huntington’s = mutations in huntingtin gene that expand a polyglutamine (Q) length
  • correlation with polyQ length and age of onset
  • long polyQ repeats cause huntingtin to form IC inclusions
    • huntingtin forms dense agglomerates within cells - called inclusions
  • long polyQ length induce huntingtin to aggregate
    • amyloid fibrils formed
    • longer polyQ, faster aggregation
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16
Q

describe the dimerisation of heterodimers.

A
  • ligand binding facilitates dimerisation and DNA binding of the receptor
  • e.g. T3 binding enhances TR-RXR and causes dissoc of TR-TR
  • heterodimerisation does not req presence of DNA, involves 2 reactions
    • C-terminal LBD and the 2nd involes the DBD
  • receptor heterodimers bind to 2 DNA 1/2 sites arranged as direct repeats
    • spacing of 1/2 sites det specificity
  • P-box in DBD makes contact with DNA
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17
Q

what is the protein folding equalibrum and how does it work?

A

unfolded-intermediately folded-folded

folded = >99%

  • to get from one conformaiton to another, required passing through transition states
  • unfolded >> folded has many intermeditates
  • proteins want to abopt lowest energy state BUT can get kinetically trapped in intermediate conformations = misfolding
  • this can shift the equalibrium towards the abnormally folded proteins which can form a “sink”
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18
Q

what is the structure of the proteasome and how are proteins degraded?

A
  • 26S proteasome
  • 19S = regulatory complex, only allows poly-Ub proteins into core
  • 20S core contains proteases
  • degradation:
    1. engagment and commitment
    2. de-ubiquitination and unfolding
    3. peptide relase –> cycle back
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19
Q

what are the type I and II nuclear receptors?

A

type I

  • classic steroid receptors e.g. sex hormones
  • undergo nuclear translocation upon ligand activation
  • in cytosol
  • bind as homodimers to inverted repeat DNA half sites

type II

  • e.g. TR and RXR
  • often retained in nucleus in absence of ligand
  • usually bind as heterodimers with RXR to direct repeat DNA half sites
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20
Q

describe the binding of hormone to NR.

A
  • ligand-binding domains of NR contain 12 alpha-helical segments
  • ligand binds Hb pocket involving helices 3,4,5
  • ligand binding causes helix 12 to fold and form a cap on lig binding pocket
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21
Q

how is co-aggregation implicated in neurodegnerative diseases?

A
  • aggregation comproises other proteins
    • co-aggregation with essential proteins
  • co-aggregation = toxic gain of function
  • aggregates interfere with these proteins normal functions due to sticky nature
  • i.e. Hungtintin’s disease
    • co-aggregation of cellular components
    • chaperones, proteasome compoents and TFS
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22
Q

describe the de-regulation of cell cycle control checkpoint genes in cancer.

A
  • amplifcation and overexpression ofn cyclins D and E1
  • decreased expression of CKI - p27
  • mutation of cyclin/CDK substrate and tumour suppressor protein pRb
    • uncontrolled G1/S phase progression
  • mutation of CHK2 gene
  • mutation of p53 gene (suppressor)
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23
Q

what are the general structural features of amyloid proteins?

A
  • amyloid = a key conformation resulting from abnormal folding pathways
    • very stable, hard to get rid of
  • generic structural motif characterised by fibrous morphology
  • amyloid have β-sheet core
  • all proteins can form this structure - slowly accumulated
  • end product >> neurodegenerative diseases
    *
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24
Q

what is the Ub-proteasome pathweay and what do the E-ligases do?

A
  • Ub targets proteins –> proteasome
  • linkage of proteins to Ub chains in specific covalent modification via Lys
  • Ub-proteasome pathway:
    • E1: ubiquitin activating enzyme
    • E2: Ub conjugating enzyme
    • E3: Ub-protein ligase
  • diversity of E3 and E3 ligases, only one type of E1 ligase
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25
Q

how does TSH increase T3/T4 production?

A
  • TSH increases transcripts of NIS
  • NIS couples Na+ inwards transport down a conc gradient with I- inward transport up the gradient
    • Na/K ATP maintains Na ?gradient
  • I- concentrates in follicle cells, more availability for hormone synthesis
  • TSH also stimulates TPO activity and increases TPO transciption
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26
Q

describe the steps in autophagy after initiation.

A
  1. Elongation + closure
  • the vesicle continues to grow and ultimately encapsulates the whole organelle and bulk cytosol by closing aroung them
  • new dbl-membrane bound vesicle = autophagosome
  1. maturation - autophagy fuses with existing lysosome
  2. degradation - contents of autophagolysosome are degraded and recycle
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27
Q

where is LC3 located in the cell?

A
  • diffuse in normal cells
  • brought together in autophagy
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28
Q

what is the pulse chase experiment and what is ti used to be identify?

A

pulse chase experiment

  • cells labelled with 35S-Met and 35S-Cys
  • new protein incorporates the isotope
  • degradation of isotope labelled GFR can be monitored over time
  • GFP from cell is captured and isotrop measured by SDS-PAGE

CL1 identified (C-degron) identified by pulse chase

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29
Q

what succeeds GFR activation

A
  1. activation of lipid kinase PI-3 kinase
  2. stimulates protein kinase, PKB
  3. PKB uses ATP to phosphorylate pro-death Bcl2 family member Bad
  4. Bad-P is recognised by cytosolic protein 14-3-3 and takes Bad away from Bcl2 - stopping release of CytC
    1. Bad no longer antagonises Bcl2
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30
Q

why does the ability to regulate proteostasis decreases with age?

A
  • less HSF1, less HSP
  • chaperons co-agg with huntingtin
  • pathological accumulation of aggregates
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31
Q

what is the folding funnel?

A
  • there are multiple pathways unfolded >> folded
  • all lead to single native state
  • when energy landscape is altered the slope change dramatically
  • increasing depth of valley >> kinetically trap alternative conformations
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32
Q

what are some potential points for intervention in neuronal death from ischemia?

A
  • NMDA/AMPA antagonists - especially NMDAR as it induces lethal amounts of Ca2+ influx
    • allosteric modulators failed in trails
  • NMDAR is hard to block as Glu is critical NT - activates many pro-survival pathways
  • antioxidant as stroke therapy
    • failed
    • thought to be sponge to reagents
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33
Q

what are some triggers for neuronal necrosis?

A
  • trauma
  • energy failure
  • excitotoxicity
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34
Q

what are 4 methods for identigying PK substrates?

A
  1. in vivo phosphorylation
    1. 32P-labelling cells and identification of phosphoprotein
  2. in vitro phosphor
    1. peptide libraries
    2. cDNA protein exp pools
  3. interaction analysis
    1. yeast 2 hybrid interaction screen
    2. phosphor-motif Ab’s
  4. genetic screening in yeast
35
Q

describe the process of necroptosis.

A

necrosis can be regulated by “necroptosis”

  • programmed necrosis
  • TNF activation but not apoptosis as its cell membrane is disrupted
  • observed if caspase inhibitors are used therefore blocked apoptosis
  • necroptosis pathways: increase lipid preoxidation and decrease [ATP]
  • caspase indepdendent necroptosis
  • one of initiating factors = DNA damage
36
Q

describe the regulation of cyclin/CDK by phosphorylation of Thr14 and Tyr15.

A
  • phosphorylation of Th14 by Mty1 and Tyr15 by Wee1 in ATP BS inhibits CDK activity
  • dephosphorylation of Thr14 and Tyr 15 by cdc25 (dual-specificity phosphotase) activates CDK activity
  • Thr160 phosphorylated the whole time (activation of cyclin/CDK)
37
Q

how is autophagy regulated?

A
  • enhancers:
    • some act by inhibiting inhibitors e.g. AMPK inhibits TOR that inhibs autophagy
    • JNK inhibits Bcl2 that inhibits autophagy
  • inhibitory actions of insulin-mediated singalling events
38
Q

how is ApoE implicated in Alzhiem’s disease?

A
  • apoE4 - major risk, apoE3 + apoE2 - lower risk isoform
  • each isoform has different “stability” i.e. equalibrium shifts more towards to the folded/unfolded conformation
    • apoE4 is more sensitive to unfolded conformations
  • homozygous for E4 is sig risk
  • apoE4 is more prone to aggregation ->> amyloid fibrils
  • pre-fibrillar amyloid state apoE4>apoE3>apoE2
    • misfolding pathway
39
Q

what is the general structure and features of the NR?

A

A/B domain, DNA-binding domain (C), hinge domain (D), ligand-binding domain (E)

highly conserved

features:

  • DNA binding domain contains a zine-finger motif
  • ligand-binding domain (E) contains hormone dependent activation towards C-terminal
  • in some NRs; ligand binding domain acts as repressor of transcription in absence of hormone
40
Q

why is there special consideration with autophagy in neurons?

A
  • neurons unable to divide - quality control needed because damage organelles CANNOT be lowered by redistribution to daughters cells
  • identify malfunctioning structures and assure degradation before they build up and –> toxicity
  • beside homeostasis, autophagy is used in continual remodelling to terminals required to support neuronal plasticity
41
Q

how is cyclin/CDK inactivated?

A
  • by CKI (CDK inhibitory proteins)
  • CKI binds cyclin/CDK to inhibit kinase activity
  • 2 classes:
    • WAF1 family
    • INK4 family
  • CDK regulated at numerous levels - cell cycle tightly controlled
42
Q

how to cells prevent misfolding?

A
  • chaperon system
    • prevents aggregation by shifting folding equalibrium away from misfolded forms
    • prevents agg by destroying intermediates
  • autophagy
    • prevents agg by destroying intermediates
    • destroys aggregates that form
  • inclusion formation
    • limits damage by modifiying aggregates to “detoxify”
43
Q

what are some (genomic/non-genomic) effects of TH?

A

genomic

  • metabolism in liver and muscle by increasing exp of genes encoding catabolic enzymes

non-genomic

  • activates PKC, MAPK and PKA
  • reg of phospholipid metabolism
  • reg activities of catecolamines
  • interactions of TH with receptor integrin avβ3 (angiogenesis, stimulation of MAPK via PLC/PKC)
  • in cytoplasm interact with TRα1 to reg actin polymerisation
44
Q

what is MIT and DIT?

and what do T3 and T4 consist of?

A

MIT = Tyr with one I- group
DIT = Tyr with 2 I- groups on benzene ring

T3 = MIT + DIT

T4 = DIT + DIT

45
Q

describe the cyclin/CDK interaction with pRb .

A
  • pRb = tumour suppressor protein that mediates G1-S phases progression
  • pRb binds E2F transcription factor, inhibiting E2F transcriptional activity
  • phosphorylation of pRb protein releases E2F –> transcriptionally active
    • D1/Cdk4 phosphorylates
    • E/Cdk2 further phoshorylates
  • E2F promotes transcription of genes important for S-phase e.g. DNAP
46
Q

describe ligand-dependent negative gene expression (transrepression)

A
  • some gene targets are turned off in the presence of lig
  • binding of free TR to negative response element of gene for β subunit of TSH activates transcription, T3 binding recruits co-repressors and HDAC to ↓ expression
47
Q

describe the synthesis and secretion of TH

A
  1. iodine taken up by receptor on basolateral surface by Na+/I- symporter (NIS)
    1. leaves the cell on apical surface
  2. Tg goes to ER and dimerises then goes to the golgi apparatus from completion of CHO chain, sulfation
  3. Tg travels to apical surfaces then out of follicle
  4. Tg iondinated, iodotyrosyl precursors (MIT, DIT) couple to form T3 and T4
  5. Tg recovered by micropinocytosis (endosomes). Hormone released, proteolysis starts, lysosomes finish
  6. Tg recovered by bulk intake –> lysosomes directly
  7. T4 and T3 enter blood stream
  8. the I- released from DIT and MIT is recycled (deiodination of T4>T3 occurs primarily in tissue)
48
Q

describe the general differences between apoptosis and necrosis.

A

necrosis

  • cell swelling
  • depletion of atp

apoptosis

  • cell shrinkage
  • maintenance of ATP
49
Q

what are the modes of substrate recognition of E3 ligases?

A
  • N-end rule (N-degron):
    • N-terminal residue defines efficacy of targeting to proteasome
    • internal Lys necessary for linkage
  • C-terminal degron - degron CL1 sequence
  • protein modification
    • NFKB activates genes, inhibited by IKB
    • IKB must be phosphorylated by IKK, so NFKB can be released
    • phosphorylated IKP>>Ub>>proteasome
  • ancillary ligand interactions
    • human papilloma virus hijacks cell mach and forces tumour suppressor p53 to be degraded
    • HPV E6 protein binds p53, E6-AP can then bind and Ub–> proteasome
50
Q

what are the common family of chaperons and how are they regulated?

A
  • Heat Shock Protein (HSP)
  • family involved in proteostasis
  • some constituative, some stress activated
  • regulated by HSF1, stimulates HSP activation
    • overstimulation increases life span
51
Q

what is autophagy?

A

adaptive response to unfavourable conditions, regulated self-eating process by lysosome

outer membrane of autophagosome fuses with lysosomal membrane - degraded

52
Q

what binds the glucocorticoid receptor and at which point?

A
  • cortisol binds GR monomer in cytosol
  • GRE and ERE = inverted repeats at half sites where ligand binds
53
Q

describe the stimulation of cell cycle progression in breast cancer epithelial cells.

A
  • insulin-like GF1–> activates MAPK –> Cyclin D1 activation –> promotes G1 phase progression
  • oestrogen –> increased cMyc –> cyclin E activation –> G1 progression
54
Q

what are the outcomes of necrosis?

A
  • cell death is rapid
  • cell swelling, dilation of mitochondria and ER, formation of vaculoes
  • cell membrane is disrupted and cell contents are lost, may damage neighbours and induce inflammation
55
Q

what are temperature sensitive mutants of Cdc?

A

when temp increases:

  • Cdc2ts and cdc25ts elongate
  • Wee1ts skrinks (goes through cell cycle faster)
56
Q

describe the sequence of events in excitotoxicity.

A

cell depolarisation

  1. ischemia (—> free radical release –>neuronal injury)
  2. decrease energy supply - demand not met in absence of O2
  3. ATP levels fall - decrease activity of ATP-dep processes i.e. Na+/K+ ATPase
  4. rundown of TM ion gradient >>
  5. glu release
  6. NMDA, AMPA receptor activation
  7. increase cellular [Ca2+] –> cycle, more depolarisation –> more Ca2+ (feedback loop)
  8. neuronal injury
57
Q

describe the progression through cell cycle through activation of cyclin/CDKs.

A
  • cyclin binds CDK
  • phosphorylation of CDKs on Thr160 by CAK (CDK-activating kinase) –> activation
  • KAP (kinase-associated phosphotase) can de-phosphorylate
58
Q

describer the structure of cyclin A-CDK2

A
  • unbound CDK2: ATP buried in catalytic cleft, t-loop covers cleft
  • cyclin A binding relieves blockage at entrance to catalytic cleft
  • cyclin A binds PSTAIRE and t-loop of CDK2
    • major links
  • cyclin A binding –> conformation changes, kinase activates
59
Q

describe the role of autophagy in neurodegenerative disease. in particular alpha-SN and hungtinton’s.

A
  • autophagy in neurodegenerative disease –> altered number of autophagosomes
  • up-regulation of impaired clearance

α-Synuclein

  • impairs macro-autophagy
  • implications for parkingson’s disease
  • digestion process impeded

huntington’s disease drugs

  • small molecules enhance autophagy and decrease toxicity
  • autophagy impaired in huntinton’s
60
Q

describe the inhibition of cell cycle through TGF-beta.

A
  • TGF –> less cMyc –> more p15 –> inhibits numerous cyclins
61
Q

describe the structure and maturation process of Thyroglobulin.

A
  • dimeric Tg, not accessible to iodination

maturation of Tg:

  • nucleus - transcription, capping, polyadenation
  • RER - translation, assembly, glycosylation
  • SER - glycosylation dimerisation
  • golgi - glycosylation, packaging
  • exocytic vesicle - secretion
  • microvilli choroid space - iondination, coupling
62
Q

in addition to excitotoxicity, ROS release also produces neuonal death in ischemia, describe the process.

A
  • ROS can damage cellular components i.e. lipids
  • prod increases during ischemia
  • e.g. -OH
  • ROS can be de-toxified by endogenous systems
    • toxicity when ROS overwhelm de-tox system
63
Q

what are the triggers and outcomes for apoptosis?

A

triggers:

  • less severe trauma
  • stimulation of pro-apop cytokines
  • loss of pro-survival cytokines

outcomes

  • usually slower death
  • cell mem not distrupted
64
Q

describe the role of proteases in neuronal cell death.

A
  • deradation of critical proteins may initiate or contribute to cell death by necrosis
  • proteases can target specific proteins, in all classes
  • calpains: Ca2+-activated cys proteases
    • overact of calpains in stroke
    • wide range of substrates
  • cathepsin: lysosomal cysteine proteases
    • normally recycle protein within lysosomes and process antigens
    • distruption of lysosome structure in stroke >> release of cathepines
65
Q

what is the criterea for validating that proteins are physiological PK sub’s?

A
  • sub must be phosphorylated by PK on same sites in vivo and in vitro
  • sun must be localised in same cellular compartment as PK during active period
  • phosphorylation should induce biochemcial changes in sub to mediate biological effects
66
Q

how is tau implicated in neurodegenerative disease?

A
  • tau = MT-binding protein
    • expressed in 6 isoforms(splicing)
  • normal function = involved in stabilisation of MTs
  • regualted by phosphorylation:
    • binds effectively to MT when de-phosphorylated
    • hyper-phosphorylation increases concentration of detached tau
  • phosphorylation changes conformation and promotes aggregation pathays (amyloid fibrils)
  • poss causes: unusual kinase activity, deficient phosphotase act.
67
Q

describe the structure of CKI (p27) bound to cyclin A-CDK2.

A
  • CKI makes contexts with CDK2 substrate
  • CKI inserts into the catalytic cleft of CDK2
  • p27 residues make cotnact within ATP BS
68
Q

in what state are TH functionally and metabolically active?

A

in their free state, only 0.3 %

but more T4 is freed when free is used up

bound in equalibrium

69
Q

describe ligand-dependent gene activation.

A
  • DNA binding in the presence of ligand and recruitment of co-activator
  • NR-L increases transcription of target gene
    • dimer binds HRE
  • transcriptional activation mediated mainly by LBD
  • NR-L binds DNA which sends stimulatory sig’s to general TF’s on same gene –> co-act recruitment
  • co-act recognise NR-L conformation of LBD
70
Q

describe the hormone response element binding of NR

A
  • hormone response elements eg. RARE and TRE = direct repeat sequences separated by 5 bp’s
  • TR-RXR binds HRE
  • HRE-binding is mediated by C-domain including zinc fingers which contact the DNA
  • RXR-TR-DNA interaction (active heterodimer)
    • RXR mostly on 5’ side of TR
71
Q

what is the back up plan if the cell cannot stop aggregation by chaperons?

A
  • inclusions and aggresomes
  • autophagy
72
Q

draw and describe the structure of the thyroid gland.

what are the differences between active/inactive structures?

A
  • apical surface - high SA
  • inactive :
    • large amount of colloid
    • flat cells surroundingn colloid
  • active
    • small follicles
    • more cuboidal cells
73
Q

what are the points of intervention to prevent apoptotic neuron death?

A

caspases

  • initiator or effector caspases
  • small non-peptide inhibitors, as pep difficult to admin
  • neuroprotection observed when delivered 1-3 hrs after ischemic injury

Bcl2 family members

  • targeting events at mito
  • good as there is communication b/n extrinsic pathway also
  • overexp of Bcl2 = implicated in cancer
  • Bcl2 can bind Apaf and stop caspase 9 activation
74
Q

what are the 3 different TH carriers?

A

Thyroid binding hormone (TBH), transthyretin and serum albumin

TBH = most common

75
Q

describe ligand-independent gene repression.

A
  • for steroid NRs, DNA binding is only lig-dep i.e. NR-L binds DNA NR does not
  • N-CoR and SMRT recognise unliganded conformations of NR
    • when H12 is back
  • binding of repressors to Hb pocket of NR via CoRNR box which resembles the NR box of co-act’s
  • CoRNR contains Ile or Leu XX Ile or Val
  • lig-dep change in position of H12 det repression and activation of NR
  • Co-R’s lack enzyme activity but recruit multiple HDACs to target gene
    • reverse effect of HAT
    • chromatin – compact
    • Co-R’s also inhibit general TF activity
76
Q

how is the type of death influenced by cellular/EC factos?

A
  • intensity of death signal
    • strong vs. weak
  • timing of death signal
    • transient vs. sustained
  • environment of cell at time of signal
    • hostile vs supportive
  • necrosis - more extreme signal
77
Q

what does thyroperoxidase (TPO) do in TH synthesis?

A
  • TPO catalyses 3 reactions:
    • oxidation of I- in presence of H2O2 to iodinating species
    • iodination of Tyr in Tg
    • Coupling of MIT-DIT and DIT-DIT (T4)
  • terminal glycosylation in Golgi is where TPO is packaged with Tg into vesicles
  • exocytosis –> TPO exposed catalytic cite with attached haem in follicilar lumen (hTPO - glycosylated, haemoprotein)
78
Q

describe the mechanism of Ub linkage.

A
  • E2 carriers Ub
  • E3 coordinates E2-Ub and substrate together and catalyses the conjugation of Ub onto substrate
  • covalent modifcation
  • E3 also catalyses the formation of multiple Ub chains which are connected by Lys-Gly isopeptide links
79
Q

what are 3 examples of protein misfolding in neurodegenerative disease?

A
  • Apo4 (AD) - demonstrates how folding equalibrium affects aggregation
  • Huntingtin - demonstrates how mutations can irreparably lead to misfolding and aggregation
  • Tau (frontotemporal dementia) - abnormal signalling process can directly lead to misfolding and aggregation
80
Q

describe the Par (ts) experiment involving polyQ with misfolding prevention mechanism.

A
  • Par(ts) misfolded at 25 deg, normal at 15.
  • if concurrent exp with polyQ, call capacity to keep Par(ts) folded at 15 deg is lost - NOT co-agg
  • misfolding of polyQ diverts proteostasis resources, insufficient resources to stop Par(ts) misfolding
  • stess means normal cells are compromised
81
Q

describe the features of co-activators,.

A

co-act have homology and similar properties to SRC-1, domain structure of SRC family:

  • NR boxes important for transcription (not on NR)
  • HAT activity acetylates kistones – open structure
  • position of H12 det co-act binding
  • H12, H3, H4 and H5 form Hb cleft bound by specific regions of co-act protein
  • co-activators have HAT and DNA unwinding activity
82
Q

how/where are thyroid hormones (Briefly) produced?

A

from iondination of Tyr in Tg (protein thyroglobulin)

synthesised in the follicles of the thyroid gland from Tg (precursor)

83
Q

describe the (general) intrinsive apoptotic pathway.

A

IC detection of stress

  • mitochondria involved in ATP production as well as ROS prod
  • formation of protein complexes in mitochondrial outer membrane allow release of proteins such as CytC
  • cytC outside membrane binds cytosolic proteins that initiate death events
  • cytC - in mito (normally involved in ETC) when changes localisation >> apoptosis

Cell Signalling and Neurochemistry (3 decks)

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