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ANAT 212 pre midterm > Professor Uglade Lecture > Flashcards

Professor Uglade Lecture Flashcards

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1
Q

Non polar hydrophobic amino acids

A

GLAMF VIP WC
Glycine (Gly, G)
Leucine (Leu, L)
Alanine (Ala, A)
Methionine (Met, M)
Phenylalanine (Phe, F)
Valine (Val, V)
Isoleucine (Ile, I)
Proline (Pro, P)
Tryptophan (Trp, W)
Cysteine (Cys, C)
Tyrosine is also hydrophobic due to aromatic ring in side chain (even though its in polar group)
-Cysteine can form disulfulide bonds between 2 cystein side chains in proteins (covalent bonds)

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2
Q

Charged amino acids

A

Basic (positive charge)
BLAH
L-Lysine (lys, K)
A- Arginine (Arg, R)
H-Histidine (His, H)

ADE
Acidic (negative charge)
D- aspartate (Asp, D)
E-Glutamate (Glu, E)

The charged R groups allow for electrostatic ionic interations between the acid and basic amino acids

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3
Q

what are the Uncharged Polar amino acids, and what bonds do the R groups form

A

R groups form hydrogen bonds
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S-Serine (Ser, S)
T-Threonine (Thr, T)
N-Asparagine (Asn, N)
Q-Glutamine (Gln, Q)
Y- Tyrosine (Tyr, Y)
Tryptophan (Trp, W) can also form H bonds due to NH in side chain (even though its non polar)

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4
Q

how are polypeptides made, what type of rxn is this?
-what do the side chains determine?
-What do side chains and backbone form?

A

-made by a covalent amide linkage called peptide bond (uncharged but polar)
-condensation reaction
-side chains determine charge and hydrophobicity
-side chain and backbone can form non covalent contacts with other AA

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5
Q

What are the peptide bonds like in the Polypeptide backbone, where is rotation possible?

A

-peptide bond is planar and cannot rotate
-rotation around central alpha carbon is possible (has some felxibility)

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6
Q

what are the 4 types of non covalent bonds

A
  1. hydrogen bonds (polar uncharged amino acids, Asn, Gln, Ser, Thr, Tyr)
  2. van der waals interactions (all amino acids have this)
  3. ionic bonds (polar charged amino acids, Asp, Glu, Arg, Lys, His)
  4. hydrophobic interactions (exclusion of water)(non polar amion acids, Ala, Gly, Val, Leu, Ile, Pro, Phe, Met, Trp, Cys)
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7
Q

covalent interactions

A

disulfide bonds between 2 cysteines
-cytosolic proteins normally do not have sulfide bonds

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8
Q

4 organization levels of protein structures

A
  1. primary structure- linear amino acid sequence
  2. secondary structure- local conformation patterns
  3. tertiary structure- proteins acquire function from this conformation
  4. quaternary structure- assembly of multiple polypetides into a final protein
    - amino acids peptide bonds and side chains engage in non covalent interactions to form 2nd, tertiary, and quaternary protein structure
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9
Q

secondary structure

A

-alpha helix- Results from H bonding in polypeptide backbone between N-H and C=O (formed every 4 peptides, alpha helix turns around every 3.6 amino acids)
- beta sheet- hydrogen bonds between backbone strands, very rigid, 2 types (parallel and antiparallel)
-commonly alpha helices and beta sheets

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10
Q

tertiary structure, what is the arrangement?
What types of contacts are formed?
What are the long range contacts between?
What structure do loops not have, why?

A

3-D arrangement of the polypeptide
-secondary struture elements are packed against each other to form a tetiary structure
-hydrophobic contacts between 2ndary elements
-long range contacts between residues that are far apart in the primary sequence
-loops have no secondary structure so they can be flexible

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11
Q

quaternary structure

A

-assembly of multiple polypeptides into a final protein
-interactions between subunits are very stable
-dimer- 2 polypeptide subunits
-trimer, tetramer, 5-mer, etc (oligomers- many subunits)

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12
Q

domains

A

-independently folded unit within a protein
-proteins can have one or multiple domains
-different domains in a protein often have diff, functions
-conserved in evolution
-forms non-covalent interactions with other molecules
-50-200 amino acids long
-long proteins have multiple domains (most polypeptides 100-800 amino acids in length)

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13
Q

amino acid side chain, what does it dertermine, and interact with

A
  • determines charge, polarity, and hydrophobicity
  • and interaction with other molecules (function)
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14
Q

what does sequence similarity indicate?
What does homology indicate?
what happens when polypeptides have diff sequences?

A

-homology (similarity) indicxates evolutionary conservation
-homology suggests common structure or function
-if polypeptides do not have sequence similarity they are divergent

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15
Q

Post translational modification (PTM) importance

A

-important for protein diversity, complexity and essential for regulation of protein function and cellular signaling

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16
Q

Types of PTM, what does cleaving, what do we do to side chains and N-terminus?

A
  1. cleaved into smaller pieces by petidases
  2. covalent modification of N-terminus (only modification to occur post translationally for N-terminus)
  3. covalent modification of side chains: introduce functional groups to proteins
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17
Q

Side chain modifications
What can they change? What can they create?
What are many of the modifications, what are they useful as?

A

-used for various cell functions
1. can change surface or conformaiton of protein
2. can create or block a binding site for other proteins
3. many mods are regulated and reversible
4.modifications are fast, so useful as switches
-all mods are mediated by enzymes

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18
Q

Main Types of side chain modifications

A

Phosphorylation (addition of phosphate)
methylation (addition of methyl groups)
acetylation (addition of acetyl group on lysine residue, commonly on N-Terminal)
-glycosylation, sumoylation, ubiquitination

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19
Q

PTM: phosphorylation

A

30% of proteins get phosphorlyated
-Only 3 amino acids can get phosphorylated on hydroxyl groups (SYT):
-Serine (S), Tyrosine (Y), Theronine (T)
- adding phosphoryl group changes the charge and size
-Kinases and Phosphatases are involved in this process (process is reversible)

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20
Q

what do kinases transfer?
what always particaptes in phosphor?
-what are the 3 types of kinase?

A

-transfer phosphates from ATP (donates group to serine)
-ATP always participates in phoshorphylation
3 types on kinase families:
-Ser/Thr kinases (adds grou to ser+thr)
-Tyr kinases
-dual specificity (ser/Thr and Tyr)
Example- aspartic acid and phosphoserine are very similar (neg charge, similar size, form ionic bonds)

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21
Q

phosphatases

A

remove phosphate groups
Phosphatase families:
-Ser/Thr phosphatases (removes group to ser+thr)
-Tyr phoshphatases
-dual specificity (ser/Thr and Tyr)

Example- serine and alanine are similar dephosphorylated

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22
Q

phosphopeptide bonding

A

-phosphorlyation can be signal to degrade protein, it is required for binding
-specialized domains bind to p_ser, p-Thr, or p-Tyr

example: phosphor of Thr allows for interactions eith other proteins through non covalent bonds

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23
Q

what does Acetylation of lysine change?
-What recognizes specific sequences?
What is acetylation used for, what does it increase?

A

-changes polarity (removes positive charge, no longer can do ionic interactions)
- Lysine (K) acetyltranferases (KATs) and deactylases (KDACs), recognize specific sequences
-used for signaling and metabolic effects
-increases size and changes charge
Example- lysine is acetylated and interaction with DNA will be weak and chromatin will not be tightly bound which is imp. for regulation of transcription

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24
Q

Methylation of Lysine (K) and Arginine (R)

A

-addition of 1 or 2 methyl groups to the guanidino group
- adds size to K and R
-methylation does no change charge but it changes the capacity of the protein to interat with others
-lysine can be mono, di, or tri methylated
-Lysine methyltransferases (KMTs) and Lysine demthylases (KDMs)

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25
PTM binding, what are they and what do they provide?
Acetylation and methylation provide new binding sites for proteins like phosphorylation -certain domains bind Ac-Lys, Me-Lys, Me-Arg and surrounding sequences
26
what does the folded structure depend on on the interior and exterior surface? What is most stable conformation?
-folded structure depends on hydrophobic interactions on interior of structure -polar side chains on outside surface -native state is completely folded conformation of a protein (lowest state of energy, and is determined by amino acid sequence) -side chain mods take place after folding usually
27
important interactions for folding
- secondary structure has lots of H-bonds -tetiary structure has more hydrophobic interactions based on binding
28
Is the Folding process complex and how does it affect the structure of the protein (length)? What do unfolded domains do?
-complex process -unfolded (denatured) domains have extended conformations with no 2nd, or tertiary structure -folding increases structure
29
what is the Native state, what is it stabilized by, what do some domains require?
-most stable conformation of protein -stabilized by hydrophobic contacts (exclusion of water) -some domains require ligand partner to be stable (cofactor (haem, steroid, etc) or another protein subunit)
30
what structure do folding intermediates have? what is exposed, and what is the state of the polypeptide?
-have some 2nd structure but tertiary incomplete -some hydrophobic side chains exposed -more of polypeptide is flexible/disordered
31
What are the 3 reasons that folding intermediates increase the risk of aggregation?
-Risk of aggregation: -hydrophobic regions prefer to be in contact with others -interaction with diff unfolded proteins leads to insolubility -fried egg--> hydrophobic residues interact with each other
32
when does protein misfolding occur, what can it lead to? What conditions cause misfolding?
-required ligand not available -can lead to genetic mutation---> misfolded proteins---> disease -unfavorbale conditions lead to unfolding (ex heat)/misfolding
33
How does aging effect the efficiency of protein control, and what does this lead to? What dieseases are characterized by protein misfolding?
-Aging decreases efficiency of protein quality control mechanisms (loss of protein homeostasis, harmful aggregates of misfolded proteins (amyloids)---> neurodegeneration (alzheimer, parkinson, ALS, dementia etc) -these diseases characterized by protein misfolding
34
how do mutations effect the amino acids (what are they called), and what is the effect of the mutations on the amino acid properties?
mutations can lead to amino acid sub., inerstion or deletion, or premature stop (can lead to truncated protein -some sub. can have little to no effect or greatly change properties of AA (making is pathogenic)
35
what are chaperones the main component of? What do they assist in? What types of regions do they recognize, what do they do to these regions? What are many chaperones called?
-main component of protein quality control network (assist in folding, prevent aggregation, not part of native state) -they recognize hydrophobic regions of protein, since poorly folded proteins have hydrophobic pathces, so they bind to it and give it a chance to properly bind -many are HSP (heat shock protein), highly expressed after stress
36
stress response, what are the proteins called? -when are they expressed? What do they recruit/do?
Heat shock protein (HSP, HSP70, HSP90, HSP60) -highly expressed after stress -response to stress that causes protein misfolding by recruiting more chaperones
37
Heat shock response location What does it protect against?
-cytosolic and nuclear proteins -protects against cell death
38
unfolded protein response (UPR), what is it for, what does it promote?
-ER proteins -can promote cell death if stress is to severe
39
what are inducible chaperones? When are they expressed?
-heat shock proteins, heat induces the transcription activation of specific genes (ex. dropsophila puffs indicate genes that are transcriptionally active -expressed under stress condition
40
constitutive chaperones, what do they assist in, what do they stabilize
assist in protein folding (typically expressed all the time in the cell) -hold or stabilizing hydrophobic residues -universal mechanism of homeostasis
41
factors that activate HSP what happens when transcription of HSP is upregulated?
-activated by unfolded cytosolic proteins -heat stress -oxidative damage -proteasome inhibition -transcription of HSP is up-regulated causing transcription of other genes to be downregulated -many HSPs are chaperones
42
HSP response time
-response continues after stress is removed to help cells recover -effects can last up to 24 hrs
43
What does HSF1 activate, what does the transcription factor mediate? What are the 3 domains? What is the composition of active vs inactive HSF1, what does active recognize?
-activates transcription of HSPs -transcription factor mediates the heat shock response -DNA binding domain (DBD), regulatory domain (RD), transcription activation domain (TAD) -inactive HSF1=monomer -active HSF1 is a trimer -Active HSF1 recognizes HSE (heat shock element) promoters
44
when does HSF1 trimerize? What does DBD (DNA binding domain) recognize?
-trimerizes under stress -DBD can recognize HSE when HSF is a trimer
45
HSF1 regulation 1. What does folded HSF1 mimic/bound to? 2. What do unfolded proteins do after heat shock? 3. what does HSF1 do? 4.why is HSP90 expressed? 5. How is HSF1 downregulated?
1. monomeric HSF1 is folded, but mimics unfolded protein and is bound by Hsp90 2. after heat shock, unfolded proteins compte with HSF1 for HSP90 binding 3.free HSF1 trimerizes and activates transcription 4. chaperones including Hsp90 are expressed and help fold or degrade the unfolded proteins 5.HSF1 is downregulated by binding excess Hsp90 to the monomer form
46
what are the 2 Types of chaperones
1. ATP-dependent chaperones 2. ATP-independent chaperones
47
What do ATP dependent chaperones promote? -What is the binding and release regulated by? -What families are ATP dependent?
-actively promote folding -substrate binding and release regulated by ATPase cycles -Hsp 70 familiy, hsp 90 family, Hsp 60 family (chaperonins)
48
what do ATP independent chaperones prevent and catalyze?
-prevent aggregation and can catalyze some folding steps
49
cooperation between chaperones, why do we need chaperones? Where are chaperones in the cell?
-need chaperones for protein homestasis -cytosol -endoplasmic reticulum -constitutive and inducible
50
human chaperones in cytosol What chaperones are in HSP70, HSP90, and HSP60? Which are constitutively expressed, which are not?
HSP70-HSC70 and HSP70 HSP90- HSP90 alpha and beta chaperonin HSP60- TRiC -HSP60 functions like E.colu GroEL all of these are constitutivly expressed besides HSP70, and can be induced by HSR
51
HSP70 family What is the size in kDa? -What controls the binding domain? -What is the difference for when it is ATP bound vs ADP bound? What does it bind?
-70kDa monomers -ATPase domain controls the substrate binding domain -ATP-bound-->no substrate peptide binding -ADP-bound--> the substrate binding is closed tightly on the peptide -binds short hydrophobic sequences
52
what is a co chaperone? What can some bind?
co chaperone-proteins which contact chaperones to regulate their activity -some can bind to polypeptide substrates themselves, both chaperones and co chaperones
53
what are the HSP70 co chaperones? What promotes substrate release?
DNAJ (HSP40) family promote HSP70 substrate binding -Nucleotide exchange factor (NEFs) promote substrate release
54
HSP70 functional cycle 1. What delivers substrate to ATP-bound HSP70? 2.What is hydrolysis mediated by, what does this result in? 3. what does NEF do? 4. What is opning of alpha helical lid induced by? 5. what happens to released substrate?
MHNOR M-Hsp40 mediated delivery of substrate to ATP-bound Hsp70 H-hydrolysis of ATP to ADP mediated by hsp40 resulting in closing of alpha helical lid and tight binding of substrate Hsp70 N-NEF catalyzes exchnage of ADP for ATP O-opening of alpha helical lid, induced by ATP binding, causes substrate release R-released substrate either folds to native state or repeats another cycle
55
what does DNAJ co chaperones regulated? -How many DNAJ genes in cell? What does it bind, why do we it activate it? What do specific domains determine?
-regulate HSP70 function -at least 53 DNAJ genes in human cells J domain- all have a conserved J domain -bind transiently to HSP70, activate it to hydrolyze ATP and bind polypeptide -do not bind substrate Specific domains-determine the specific biological function of gene
56
What do DNAJ bind? What do they transfer?
-DNAJ substrate binding are highly conserved -DNAJ-->J domain, substrate binding, dimerization -bind short hydrophobic sequences -transfer substrate to HSP70 during ATP hydrolysis
57
how does DNAJ bind, what does it act as? -What do some DNAJ not do? -What do some domains attach DNAJ to? What do the DNAJs recruit?
-DNAJs bind substrate through specific domains, and act as ATP-independent chaperones -some DNAJ do not bind substrate -specific domains attach DNAJ to a protein complex or intracellular membrane -these DNAJs recruit HSP70s to the complex or membrane
58
Nuclear Exchange factors (NEF) what do they remove, what does this allow for? -What does NEF open up? -What binds when NEF dissociates? -What does ATP bound HSP70 release?
-NEF remove ADP from HSP70 and allow ATP to bind -NEF binding opens up HSP70 ATPase domain and weakens interactions with nucleotide -ATP binds when NEF dissociates -ATP-bound HSP70 to releases polypeptide (multiple NEF families in humans)
59
What does HSP70 bind and what does it prevent? -What does HSP70 release, what does this allow? -What does balance between DNAJ + NEF support? -What does substrate binding DNAJ assist?
-binds hydrophobic regions of folding intermediates and prevents incorrect contacts from forming -release polypeptide from HSP70, allows chance to fold -Balance between DNAJ + NEF supports optimal rate of HSP70 substrate binding+release -substrate binding DNAJ may provide additional assistance in folding -can form multi chaperone complex with HSP90
60
HSP90 family, what are the chaperones composed of? -How does the dimer act? -What does ATP control?
-chaperones are homodimers with 2 identical subunits joined at the C-termini (human hsp90: 2*90kDa=180kDa) -dimer can open/close like a nutcracker -Atp controls opening and closing of the dimer
61
what does HSP90 co chaperone stabilize? What does it bind/when? What does it bind to/stabilize? What is substrate bound to?
SBHSD S-co-chaperone p23 stabilizes closed form B-bind polypeptides at late stage of folding (recognizes hydrophobic+phillic residues) H-binds to hydrophobic +polar surfaces--> stabilizes intermediate folded states S-substrate is bound along the sides of the subunits D-different substrates can bind to diff sites on the sides (unlike HSP70 + chaperonins)
62
HSP90 functional cycle -When is the substrate bound weakly? -What does ATP binding allow? What does ATP hydrolysis do?
1. substrate bound weakly in the open nucleotide free state 2. ATP binding allows dimer to close and bind substrate tightly 3. ATP hydrolysis to ADP compacts the dimer and releases substrate
63
HSP70-HSP90 co chaperone system, where does it form? -what does it assist? -What is substrate released from and bound to?
-cytosolic HSP70 and HSP90 form a multi chaperone system -cooperate to assist substrates -substrate is released from HSP70 and bound by HSP90 in coordination
64
HSP70-HSP90 co chaperone system, what does HOP assist in? -When does HSP70 dissociate? -What do co chaperones provide/act on? What happens when folding is not complete?
-HOP assists complex formation -HSP70 dissociates when HSP90 binds ATP -Many co-chaperones regulate HSP70 and HSP90 -co chaperones sometimes act on substrates -provide flexibility -folding and non folding functions -if folding not complete in first round it goes through 2nd cycle
65
HSP70+HSP90 have EEVD motif What do cytosolic HSP90 and HSP70 have in common? -What recognizes these EEVD motifs?
Cytosolic HSP70 +HSP 90 are not homologous but share EEVD c-terminal sequence motif -TPR domains recognize these EEVD motifs (glutamic acid (E), Aspartic acid (D), Valine, (V)) -can be HSC 70, HSP 90 or both -motifs= afew amino acids that are conserved
66
TPR co chaperones What are some TPR co chaperones?
TPR domains are adpators to HSP70 + HSP90 -often have a domain which interact with substrates directly includes (FHC): -FKBP52 -CHIP -HOP
67
what type of co chaperone is HOP? What does it have/bind?
TPR co chaperone- has domains that bind HSP70 and HSP90 specifically
68
what is FKBP52, waht does it have? What is PPI? What are prolines?
co chaperone- has an HSP90- binding TPR domain, and PPIase domains -peptidyl-propyl isomerase:chaperone specific prolines -prolines are special amino acid that has a ring which doesnt matter what formation it is in cis/trans (typical polypeptide=trans formation)
69
what type of co chaperone is CHIP? What does it bind/what domain does it have? -What is a U box
TPR co chaperone- binds HSP70 or HSP90, and has a ubiquitin ligase domain that helps degrade the protein -U-box= sends proteins for degradation when ubiquitin is present
70
HSP90 and signaling What are the substrates/signals? What may this also require? What does HSP90 bind without the help of? What do mutations cause?
-many substrates are signal transduction proteins -kinases, receptors, transcription factors -may also require HSC70 -except:HSP90 binds kinases without the need of HSC70 -mutations in signaling protein cause cancer -HSP90 and HSC70 are drug targets for cancer treatments
71
what does V-src cause, what is it? c-src, what is it, what is it involved in?
V-src= viral mutant kinase that causes cancer (HSP90 supports this viral form) c-src= cellular normal kinase involved in signaling cell growth
72
How to fix V-src 1. Where is V-src expressed, what does it cause? 2.what do you treat it with? 3.What happens to hsp90? 4. what do cells revert to? 5. How does HSP90 hold HSF1, what happens if no HSP90?
1. v-src expressed in fibroblast (epithelial) cells causes them to become cancerous 2. treat with hsp90 inhibitor 3. hsp90 cannot chaperone v-src anymore 4. cells revert from cancer to normal growth side note:HSP90 holds HSF1 as a monomer, if no hsp90, you will activate factor of HSF1 to express more HSP
73
what are chaperonins (HSP60 family) composed of? What is Gro EL composition? WHat is GroES composition?
-large oligometric complexes, with typical double ring structure -e coli Gro EL: 2 rings * 7 identical subunits*60 kDa=840 kDa -E coli GroES cap chaperone: 7 subunits * kDa=70 kDa -homologs of human mitchondrial Hsp60 and hsp10
74
GroEL cavity -How are the rings related and how do they work? -What occurs in the down position, what do subunits bind to? -What occurs in down position, what do subunints bind to? What type of cavity/surface is formed in up position, what is released?
-rings are identical and work in alternating cycles -down position ( no nucleotide) -subunits around the ring bind to hydrophobic polypeptide -up position (ATP-bound) -subunits bind to GroES cap instead of substrate (when HSP60 is bound to ATP it can bind to GrosES) -large cavity with a polar surface is formed -substrate is released inside cavity:enclosed but not bound
75
What do GroEL subunits have? -What ATPase domain the interface for? -What is the movement of substrate controlled by?
-Each GroEL subunit has and ATPase domain and substrate binding domain -ATPase domain is the interface with the opposite ring (upside down) -movement of the substrate binding domain is controlled by the ATPase in both rings
76
GroEL folding part 1 What is substrate enclosed in, what does it provide? -What does the confinement promote? What releases the substrate/how does it act?
substrate is enclosed inside polar cavity -provides chance to fold -confinement promotes folding by favouring more compact conformations -ATP hydrolysis acts as a trimer for substrate release

ANAT 212 pre midterm (9 decks)

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