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cell bio > section 12 Atypical organelleles like mebraneless ones (MLO) > Flashcards

section 12 Atypical organelleles like mebraneless ones (MLO) Flashcards

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Biology 101 flashcards
1
Q

compartment separation without membranes

A

*liquid-liquid phase separation

  • lava lamps, vinaigrette salad dressing, nucleoli
  • one liquid within another liquid (droplet/plastic conformation + dynamic)
  • 2 immiscible liquids = apply the force of shaking and one in the background of the other (cannot dissolve sitting)
  • dynamic in size, shape, number, contents, etc.
  • some stuff can come in and some stuff can come out
  • can occur in the nucleus and cytoplasm
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2
Q

nucleolus as an example of compartment separation without membranes

A
  • different compartment in the nucleus (liquid-liquid separation)
  • no membrane
  • phase separated by MLOs (membrane-less organelles)
  • during mitosis it disperses and then reorganizes

*more dynamic (contents and traveling in and out) than membrane-bound

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3
Q

membrane structuring of Membraneless Organelles (MLO)

A

protein component, metastability, glass/gel, and fiber,

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4
Q

protein component

A

can move in and out (more dynamic than membrane organelles)

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5
Q

metastability

A

fine and normal (reversible) - come in and come out and change shape

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6
Q

glass/gel and fiber

A

pathology when contents move onto higher organization order –> detrimental

  • we know that it can go to higher organizations but we are not sure if it can be reversed by drugs or natural cell
  • further organization is bad because of protein arrangements rather than soluble proteins

*soluble –> fibrillar bad (positive) but not sure about the reverse - pathology with protein

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7
Q

diversity of MLO

A

function, structure, nucleolous, P-body

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8
Q

MLO function

A

associated with cell division, chromatin remodeling, gene transcription, synapse function, virus assembly, diverse contents, duration & size (any cellular process probably has MLO associated)

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9
Q

MLO structure

A

include P-body and nucleolus (classic examples) but variable in different cells

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10
Q

nucleolus (MLO)

A

disassembly/reassembly with cell division

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11
Q

P-body

A

RNA breakdown; variable duration depending on growth conditions - may arise or disperse

  • P-body more present during RNA breakdown (not present in all cells)

*often sites of catalytic activity (not passive) and dynamic (dispersion)

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12
Q

examples of MLO diversity

A
  • virus factory = COVID, HPV, etc. assemble progeny virus
  • Tp53 aggregation

*variability of what MLOs are in cells (except nucleolus in most)

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13
Q

p-body (function)

A

processing/breakdown of RNA

  • may arise or disperse in different cell types
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14
Q

MLO: generate new compartments

A
  • cytoplasmic granules, form & fuse cytoplasm purple; granule green = droplets fuse and grow (conditions drive larger MLOs)
  • subnuclear compartments
  • vary based on growth, nutrient, time, etc.
  • variability based on size, what they do, in their content
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15
Q

MLO:reorganize existing compartments

A

separating out components (not nucleoli) for self-association and organization - subnuclear

  • nucleoli fusion = dynamic nucleoli fuse (no membrane, only RNA protein composition)
  • subnuclear compartments in the nucleolus that are forming because of liquid-liquid
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16
Q

MLO: vary in time, location & size

A
  • cytoplasm, nucleus, nucleolus (<0.5 frequent - ~20um rare)
  • time is taken to disperse or form variable
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17
Q

compare and contrast membrane-bound and MLO organization (function)

A

optimized function (specialized subcompartment)

  • lysosome = acid hydrolase efficiency (bound)
  • mitochondria = electron transport, H+ gradients (bound)
  • P-body = (processing body) RNA decay (membrane less)

*share the ability to function within

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18
Q

compare and contrast membrane-bound and MLO size and shape

A
  • nucleus = 5-10 um diameter
  • nucleolus = 0.5-2.5 um diameter
  • other MLO = <0.5 frequent - ~20um rare

*what binds the perimeter?

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19
Q

membrane-bound “organizer”

A
  • phospholipid bilayer(s)
  • boundary from aqueous cytoplasm
  • for specialization
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20
Q

membrane-less “organizer”

A
  • protein biochemistry
  • characteristics more likely to self-interact than interact with aqueous cytoplasm
  • protein phase separate from the environment (not compatible with protein biochemistry)
  • partnered proteins associate, leaving out proteins less likely to interact
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21
Q

MLO formation

A

*LLPS - liquid-liquid phase separation

  • dissolved proteins interact with each other, and possibly RNA to coalesce (de-mix) from surrounding homogeneous mixtures of diverse macromolecules in cytoplasm or nucleoplasm (dispersion into nuclear shadow)
  • reversible depending on stimulus = compare to separation (re-mixing oil-water) and very variable time

*nuclear shadow excluded (organized) and dispersed rapidly but can organize back

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22
Q

MLO diverse examples for formation

A

cajal nuclear bodies and PML nuclear bodies

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23
Q

Cajal nuclear bodies

A
  • varied content & function
  • partially regulate transcription
  • process (association with) RNA for spliceosome assembly
  • increase the efficiency of nuclear events like RNA processing
  • nuclear events (mRNA)
24
Q

PML nuclear bodies (green dots ~.2um)

A
  • PML protein: replication suppressor
  • ~100 possible partner proteins in different PML bodies for varied functions (apoptosis, telomere elongation)
  • always have PML protein
  • nuclear functions differ depending on partner protein but relate back to PML (most varied)
25
Q

LLPS concepts

A
  • protein condensation leading to…
    - subfunctions
    - reaction crucible
    - sequestration
    - organizational hub
  • 3 variations (different major subtypes, subfunctions of membrane-less organelles)

*associated with happy, healthy cells

26
Q

sequestration

A
  • storage for later processing or secretion (deposit/reservoir)
  • reduces response time to extracellular signals (physiological response decreases lag time)
  • secreted, processed at later event
  • premade proteins in preparation for physiological change
27
Q

organizational hub

A

*physical association

  • normal condensation of proteins (ex. MT, tau) to focus interaction/polymerization of partner proteins (microtubule stability)
  • 2 or more proteins physically associate to build a structure to increase cell
  • advance cell
  • more efficient if physical components inside MLO
28
Q

scaffold vs. client proteins

A

scaffold proteins
- can drive LLPS on their own
- enriched for domain repeats
(multivalent) & little 3D structure
(disordered)
- sufficient concentration will condense
+ separate from the surrounding
plasma (cyto or nuclear)

client
- proteins can interact with scaffold proteins
- compatible with LLPS of partner proteins
- typically insufficient for LLPS on their own

29
Q

protein characteristics for LLPS - driving phase separation (scaffolds)

A

multivalent and disordered

30
Q

multivalent

A
  • repeated subdomains = repeated site for interactions (amino acid series, etc.)
  • drives condensation of MLO (because of multivalent for another protein)
  • scaffold for partner protein
  • ex. SOS & Grb2 (PRM & SH3 subdomains)
  • protein-protein recognition for partner-building droplet
31
Q

disordered (not the same as denatured)

A
  • no rigid 3D “lock & key-type” conformation
  • do not have 1 defined 3D structure (shape-shifting dependent on partners, etc.) - flexibility
  • hi content of polar & charged amino acids = keep protein in extended shape
  • low content of hydrophobic AA = less likely to fold up to reduce interaction with water
  • reconfigurable (not rigid or dimensional)
  • flexible, interact with many partners
  • floppy end
  • interact with nucleic acids (RNA binding protein has flexible disordered region allowing it to interact) - drives the formation of MLO (smaller than nucleolus)- no rigid 3D “lock & key-type” conformation
32
Q

phase separation of LLPS extracellular conditions

A
  • pH, osmolarity, etc.
  • stressors like toxins (environmental stress)
  • take homogeneous proteins –> cause some to come out and phase separate
  • change extracellular to get a response inside the cell
  • ex. cytoplasm –> cytoplasm with condensates
33
Q

phase separation of LLPS intracellular conditions

A

*cause condensation

  • protein concentration
  • ion concentration
  • partners (other proteins, RNA, or DNA)
  • ATP (as charged molecule; not as an energy source)
  • post-translational modifications (ex. phosphorylation increasing p-tau (increasing separation) –> MT depolymerization)
  • for some proteins, possible disease-specific mutation
  • more individual protein –> most likely to dissociate
34
Q

t/f) condensates redirect cell activity

A

true; reaction crucible, sequestration, organization hub

35
Q

phase transition

A

*LLPT - liquid-liquid phase transition

  • different than separation
  • may occur abruptly after LLPS
  • excessive interactions among components
  • uncertain reversibility, uncertain consequences - may intervene with a drug compound (drive reversal)
  • possible disease - denser and denser protein assemblies
36
Q

proteins dispersed –> separation

A
  • self associating
  • phase separation
  • normal cell physiology –> normally reversible (back to dispersed)
37
Q

aggregation

A
  • may occur independently or following LLPT
  • disrupts normal cell function
  • abnormal, often disease-associated and typically irreversible
  • ex. dispersed & aggregated tau

*pathological consequence from transition –> aggregation

38
Q

separation vs. transition vs. aggregation

A
  1. dispersed well
  2. MLO from LLPS good (normal cell physiology) = associated MLOs
  3. transition unsure (unsure if we can go back)
  4. aggregation is bad and known to be irreversible
39
Q

interaction beyond LLPS bad news

A
  • function –> dysfunction
  • all neurological examples but can be anywhere (dramatical clinical presentation of aggregated proteins in neuropathology)
  • can occur in lots of different cell types in lots of different cells
  • aggregation, nucleation

*likely irreversible nature of assembly (amyloid) and insoluble

40
Q

dispersion to aggregation

A

*disperse –> LLPS –> LLPT –> aggregation

  • condensation from excess interactions = generates “solid” structures, insoluble, fibrous “amyloid”
  • fibrils, tangles, etc. associated with many degenerative diseases
  • characteristics or cause of dysfunction?
41
Q

nucleation

A

aggregated proteins serve as condensation foci for proteins that would otherwise remain in LLPT or move back to LLPs

42
Q

example pathologies & dysfunctional proteins

A

*dramatic - several proteins associated with the neuropathologies transition to the aggregation phase

  • amyotrophic lateral sclerosis (ALS, Lou Gehrig’s disease) = TAR DNA binding protein-43
  • Alzheimer’s disease (AD) = microtubule-associated tau
  • Parkinson’s disease (PD) = a-synuclein amyloid fibrils from LLPT –> amyloid clumps
43
Q

a-synuclein normal role

A
  • vesicle delivery to cell termini
  • neurotransmitter deliver and release at the synapse
  • found in the cytoplasm under the membrane at the synapse (in the nucleus)
  • undefined role in the nucleus
  • normal day-to-day functioning delivering neurotransmitters
  • issue when transitioning to aggregation phase (amyloid fiber clumps - Parkinson’s disease)
  • several proteins associated with new neuron
44
Q

a-synuclein example

A

*potential to clump into amyloid fibers

  • normal function - self-associating, delivering to the synapse, etc.
  • individual proteins –> LLPS (normal function) –> increased self-interaction –> LLPT (forms aggregate) –> aggregates –> amyloid fibrils (disruption of neurotransmitters and dysfunction of the neuron)
  • Parkinson’s disease
  • decreased vesicle trafficking
  • disrupted transmitter release

*pathology in phase separation to phase transition

  • timing and progression vary
45
Q

(t/f) insufficient amount of protein also causes pathologies

A

true; not just more protein to transition (excess protein –> phase transition –> dysfunction) but function missing if insufficient amount

46
Q

exploring therapeutic interventions of MLO and LLPS/LLPT dysfunction (locations)

A
  • LLPS/T locations: nucleus and cytoplasm (possible impact on many cell functions & therefore many diseases)
47
Q

Exploring therapeutic interventions of MLOs and LLPS/LLPT (dysfunction)

A

dysfunction type

  • insufficient interactions for LPPS & therefore no “reaction crucible, storage, or hub”
  • excess interaction driving LLPT (multivalent with self or partner)
    - partner excess or missing
    - wrong type or timing of post-
    translational modification
48
Q

Exploring therapeutic interventions of MLO’s and LLPS/LLPT ( pathologies)

A

resulting diverse pathologies

  • neurodegeneration (TAR43, p-tau, a-synuclein)
  • hyperplasia/cancer (p53, myc, p53)
  • other tissue degeneration
49
Q

neurodegeneration therapeutic interventions

A
  • protein aggregates driving drug discovery
  • variations of ZPD
  • small molecule compound (pre-clinical drug) = inhibit nucleation and aggregation (prevent late phase only if you get to it in time)
  • inhibits aggregation and promotes disassembly (reverse phase transition)
  • simplifying ZPD chemistry - that interacts with a-synuclein protein to make more compatible with clinical use
50
Q

drug interaction with protein 1 (therapeutic interventions)

A

facilitates LLPS for reaction crucible, sequestration, organizational hub (organization)

51
Q

drug interaction with protein 2 (therapeutic interventions)

A

reduce LLPS that might be precursor of LLPT and/or aggregate (disperse to more compatible with normal cell physiology)

52
Q

drug regulation of modifier (therapeutic interventions)

A

regulate post-translational modification for a desired effect (protein dispersion)

  • the drug may impact the modifier

*protein molecule some structure, some disorder (foldable + flexible region)

53
Q

gene expression - review material

A
  • DNA gene –> mRNA transcript –> function or structural protein –> cell activity or structure –> organ activity/structure –> organism
  • transcription of DNA in the nucleus into RNA
  • rRNA ribosomal RNA - polymerase I
  • mRNA messenger RNA - polymerase II
  • tRNA transfer RNA - polymerase III
54
Q

RNA pol II

A

*reads 3 nucleotides per codon, with 4 nucleotides available

  • more than enough to cover the 20 encoded amino acids
  • DNA gene –> mRNA transcript –> protein
  • consequences of mutations
55
Q

mutations - review

A
  • mutations change coding sequence
  • may occur in somatic or reproductive cells
  • can occur spontaneously (DNA polymerase error) or by radiation or chemical exposure
56
Q

mutation example 1

A
  • nucleotide substitution
  • may result in replacement of one aa with another
  • example - sicke cell anemia allele single base change in DNA results in aa change in hemoglobin
  • or no change if new codon codes for same aa (coding redundancy)
57
Q

mutation example 2

A
  • insertion or deletion of bases in DNA sequence
  • results in phase shift of three base reading frame
  • affects all codons after mutation
  • results in different amino acid sequences
  • almost always results in a non-functional polypeptide

cell bio (4 decks)

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