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MBM > Regulation of Gene Expression > Flashcards

Regulation of Gene Expression Flashcards

1
Q

What did the human genome project reveal about the human genome?

A
  • it has fewer genes than was previously thought, less than rice and corn
  • number of genes is less important in determining complexity than how expression of genes is regulated
  • network of interactions
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2
Q

What do transcription factors do once activated?

A

turn on expression of a set of genes that all have its binding site in their promoter/regulatory regions

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3
Q

Positive feedback loop in expression? What can this contribute to?

A

transcription factors activate expression of their own genes, contributes to cell memory

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4
Q

What is transcriptional regulation?

A

regulation of availability or activity of transcription factors

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5
Q

What regulates epigenetic signals?

A
  • histone/chromatin modifications

- DNA methylation

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6
Q

What is the rate limiting step in transcription?

A

initiation

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7
Q

What does the rate of transcription affect in terms of proteins?

A

affects the amount of protein produced from a gene

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8
Q

What mediates responses to environmental signals in regulation of transcription?

A

signal transduction pathways that can influence the availability and activity of transcription activators

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9
Q

What are some external factors that influence transcription?

A
  • steroids
  • growth factor
  • hormones
  • calcium
  • cytokines
  • UV light
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10
Q

Epigenetic signals are maintained during what process?

A

DNA replication

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11
Q

How does epigenetic signals influence gene expression through effects on chromatin structure?

A

by regulating the accessibility of DNA to transcription factors, making chromatin too tight or too loose

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12
Q

Why are most epigenetic signals not passed on to the next generation?

A

most are erased during production of germ cells, but there is evidence to suggest that some can be passed through multiple generations

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13
Q

What does mitotically heritable mean?

A

passed on in somatic cells during mitosis, but not passed in germ cells

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14
Q

What types of post translational modifications of histones regulate gene expression? How?

A
  • acetylation (activation)
  • methylation, (di and tri)
  • monoubiquitination
  • phosphorylation
  • context dependent
  • chemical groups can be added to histone tails
  • they affect the strength of interactions between histones in different nucleosomes, between histones and DNA, and between histones and other proteins
  • the affects on chromatin structure determine how easy or hard it is for transcription factors to access DNA
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15
Q

DNA methylation is associated with mitotically heritable gene _________.

A

inactivation

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16
Q

DNA methylation is required for what processes?

A
  • normal development
  • X chromosome inactivation- one copy off
  • imprinting
  • reinforces gene regulatory decisions brought about by other mechanisms
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17
Q

What is imprinting?

A

one allele is turned off

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18
Q

Why is DNA methylation important?

A
  • cellular differentiation
  • determining tissue specific patterns of gene expression
  • maintain chromosomal stability, tissue specific
  • involved in more dynamic types of gene regulation (sparse CpG in TSF binding sites)
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19
Q

How does DNA methylation maintain chromosomal stability?

A

by keeping repetitive sequences in non coding regions in a repressed state

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20
Q

What are DNA methyltransferases?

A

enzymes that add methyl groups to CpG

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21
Q

What is DNMT 1?

A
  • maintenance methylase

- responsible for maintaining established methylation patterns during DNA replication

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22
Q

What are DNMT3a and DMNT3b? Function?

A
  • de novo DNA methylation
  • methylate promoter regions of genes to turn off expression when their proteins are no longer needed as cells differentiate
  • can sometimes be recruited to promoters by TFs to play more dynamic role in gene regulation at sparse CpG sites
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23
Q

How do DNMT3a and 3b help with a more complete turn off of gene expression?

A

turns off ones already not expressed which shuts down basal TFs for a more complete turn off

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24
Q

Methylated promoters are active or inactive? explain.

A
  • inactive

- active promoters cannot be densely methylated

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25
Q

How do methyltransferases and histone modifying proteins have reciprocal interactions?

A

De novo DMNTs are recruited by histone modifying proteins, and histone modifying proteins are recruited by proteins that bind methylated DNA

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26
Q

What enzyme are involved in demethylation?

A

Ten eleven translocation enzymes (TETs)

-led to belief that methylation is more dynamic than previously thought

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27
Q

How do TETs remove DNA methylation? Passive vs active?

A
  • remove it by successive oxidation of 5-methyl cytosine
  • passive= create versions not recognized by DMNT1, failed maintenance
  • active= form versions that are recognized as damage and removed by base excision repair enzyme, methyl removed
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28
Q

Where are TET enzymes more abundant?

A

in early embryonic stem cells and germ cells, also found in low levels in somatic cells

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29
Q

What is the first intermediate in demethylation? where does it play a more active role in gene regulation?

A
  • 5 hydroxymethylcytosine
  • brain
  • may protect cells from abnormal DNA methylation
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30
Q

DNA methylation works together with repressive histone modifications to create what?

A

a more stable form of heterochromatin inaccessible to TFs

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31
Q

When the cell divides, what maintains repressed chromatin and the methylation pattern? What does this create in terms of stability?

A
  • DMNT1 (maintenance) and the histone reader writer complex

- create a meta-stable state, over time, can be changed

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32
Q

DNA methylation correlates with ______ of histones, and the formation of _____chromatin.

A

deacetylation

hetero

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33
Q

What is the process of histones becoming more methylated and meta stable? What genes are heavily methylated?

A
  1. DMNT is attracted by histone reader writer protein
  2. methyl binding protein makes the repressed state more stable
  3. methylated CpG become very tight and protected

-only inactive genes are heavily methylated and more permanently inactivated this way

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34
Q

Meta stability?

A

maintained long term, but retains the potential to be modified

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35
Q

What does the deamination of methyl cytosine create?

A

thymine

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36
Q

What are CpG islands? Are CpG sequences represented well in the genome?

A
  • regions rich in CpG sequences, 1 to 4 kbs long usually in promoter region of first introns of genes
  • CpG have become underrepresented in the genome, not spread evenly throughout
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37
Q

Where are CpG islands normally found? Are they normally methylated?

A
  • 5’ regulatory regions of some genes, especially housekeeping genes that constitutively expressed
  • promoter regions or first introns of genes
  • 90% are not normally methylated, maintained through evolution
  • some are methylated in a tissue or differentiation stage specific manner
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38
Q

What happens with the inappropriate methylation of CpG in the promoter regions of certain genes?

A
  • cancer
  • tumor suppressor genes shut off
  • genes encoding proteins involved in DNA repair or apoptosis shut off
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39
Q

During the course of evolution, most CpG sequences in the genome have been mutated to what?

A

TpG

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40
Q

What are CG rich areas in other genes used for?

A
  • involved in regulating expression by DNA methylation

- affects whether or not certain TFs can bind due to recruitment of de novo methylases to promoters

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41
Q

What is genomic imprinting? How many genes does it affect? Most of the genes affected are involved in what? Where are they often found?

A
  • mono allelic gene expression in diploid cells- limit dosage of certain genes, turn one allele off
  • specific to parent of origin
  • affects only a few hundred genes
  • involved in regulating embryonic and neonatal growth
  • often clustered with non coding RNA, which are involved in regulating imprinting process
  • Insulin type 2- maternally imprinted, turned off
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42
Q

Maternal vs Paternal imprint?

A
  • maternal- fetal growth, moms genes turned off

- paternal- distribution of resources, dads genes turned off

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43
Q

Passing imprints to the next generation happens during gametogenesis in two phases, describe them? What does the incomplete methylation say about epigenetic being passed down?

A
  1. in primordial germline, demethylation is followed by methylation to establish sex specific imprint patterns
  2. after fertilization, there is global demethylation in the embryo before implantation, and then global methylation after implantation
  • most imprinted genes, 2nd phase of demethylation in zygote doesn’t occur, pattern in gametes is maintained
  • methylation is incomplete which means that epigenetic patterns can be passed down due to environmental factors
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44
Q

How many generations is needed to observe transgenerational inheritance of epigenetic signals?

A

three

-nonimprinted genes can sometimes escape reprogramming in embryo

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45
Q

Explain the concept of developmental plasticity? Dutch hunger study?

A
  • DNA methylation of non imprinted genes occurs in embryo as cells differentiate which turns off expression of genes whose products are no longer needed, cell and tissue specific changes occur
  • in utero environment influences epigenetic signals which allows modification of certain phenotypes to make offspring better adapted to the situation it will be born into
  • dutch study- starved women in first trimester of pregnancy, then returned back to normal diet, this established pattern of methylation in-utero, the offspring were more prone to obesity, cardiovascular disease and insulin resistance
  • Leningrad famine- people had lower risk of heart disease because famine persisted
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46
Q

What is the fetal basis of adult disease theory or thrifty phenotype hypothesis?

A
  • metabolic disorders have a developmental origin related to early nutrition during gestation and lactation
  • fetal under nutrition and low birth weight are associated with increased risk of diabetes, congestive heart failure and stroke
  • effects accompanied by epigenetic signals
  • increased insulin resistance
  • advantage if famine conditions persists, but if abundance of food it is a disadvantage
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47
Q

Why would malnutrition during pregnancy cause children to have problems when food is abundant?

A
  • causes increased insulin resistance which is a survival advantage during malnutrition, but a problem when food is abundant
  • insulin is not able to lower blood sugar enough, causes heart problems
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48
Q

Epigenetic drift? Twins? Why does this happen?

A
  • levels of DNA methylation change with age (tend towards demethylation)
  • twins have similar levels of methylation at birth, but become different as they age or spend time apart
  • partly due to imperfect maintenance of DNA methylation over time, environmental influences
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49
Q

What can be used to predict the biological age of individuals?

A
  • methylation status of a set of particular CpGs in peripheral blood
  • rate of epigenetic drift correlates to increased mortality
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50
Q

DNA methylation is erased where? Then reestablished where? Cell type specific changes in methylation are linked to what?

A
  • germ line and blastocysts
  • early in development
  • cellular differentiation
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51
Q

Major changes in DNA methylation are associated with cancer, smaller changes are associated with what?

A

chronic inflammation or obesity

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52
Q

What does it mean that epigenetic signals are metastable?

A
  • although, methylation is mitotically heritable and regarded as a way to shut off gene expression, it can be reversible in some patterns over time
  • fewer changes in methylation = epigenetically young and healthier
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53
Q

What is SAM (s-adenosyl methionine)? Where is it found and how is it synthesized?

A
  • universal methyl donor, used to methylate both DNA and histones
  • made from methionine through a process called one carbon metabolism which requires Folate and B vitamins (might be feeding established tumors)
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54
Q

What does Acetyl CoA do to histones? Where is it produced?

A
  • provides acetyl groups for histone acetylation

- produced from metabolism of carbs and fatty acids

55
Q

What links have been found between epigenetics and nutrition?

A
  • SAM
  • Acetyl CoA
  • affect microbiome, some bacteria produce substances the inhibit HDACs
  • dietary phytochemical can influence activity of epigenetic effectors such as HATs, HDACs, DNMTs (epigenetic diet)
56
Q

What does an epigenetic diet inhibit? What are the effects?

A
  • inhibits HATs, HDACs, DNMTs, regulate mRNA

- decreased cancer, increased longevity, decreased age related diseases

57
Q

What are three forms of post transcriptional regulation?

A
  • alternative splicing
  • regulation of mRNA stability
  • RNA editing
58
Q

What is the point of alternative splicing? What percentage of genes are alternatively spliced?

A
  • limit amount of protein made

- 75% of genes

59
Q

What is constitutive alternative splicing? When does it happen? Sequences involved? How many versions of the protein are made?

A
  • happens all the time
  • results from intron sequence (consensus) ambiguity and limiting amounts of splicing factors
  • some sites are better than others, they are recognized first
  • several versions of the protein are made in the same cell at the same time
60
Q

What is regulated alternative splicing? What does it involve? Where does it occur? What does it depend on? How many versions expressed?

A
  • tissue or developmental stage specific
  • involves addition or removal of a functional domain of the protein, part of protein has particular function
  • depends on splicing activators or repressors
  • usually one version of protein expressed in the cell
61
Q

Explain positive control in regulated alternative splicing?

A

the pre-mRNA transcript normally is not spliced, but an activator is placed on the transcript which signals splicing to take introns out

62
Q

Explain negative control in regulated alternative splicing?

A

the pre-mRNA transcript is normally spliced, but a repressor is placed on the transcript which signals no splicing to occur, introns remain in the transcript

63
Q

What is an example of alternative splicing?

A
  • splicing of mRNA encoding kinase: alternative exons target the protein to different cell locations
  • may go to membrane, nucleus, or cytoplasm and perform a different function
64
Q

What is the usual first step in mRNA degradation? What direction is the decay? Can decay occur in the other direction?

A
  • deadenylation-shortening or removal of poly A tail
  • decay in the 3’ to 5’ direction
  • yes, deadenylation can also trigger recapping and decay in the 5’ to 3’ direction
65
Q

What is the result of mRNA with a longer half life? What mRNAs typically have longer half lives? Do most have long half lives? Which mRNAs have short half lives?

A
  • more protein can be translated from it because it takes longer to degrade, more efficient
  • long half lives: housekeeping genes like beta-globins=hemoglobin in RBCs
  • most have short half lives: mRNAs encoding growth factors, regulatory proteins whose expression levels need to change rapidly
66
Q

What does the rate of degradation or deadenylation depend on? What elements increase the rate of deadenylation?

A
  • depends on 3’ untranslated regions (UTRs) to increase or decrease degradation
  • AUUUA elements increase the rate of shortening of the poly A tail
  • RNA surveillance (nonsense mediated decay NMD) triggers fast degradation or defective mRNAs
  • endonucleases cleave off tail
67
Q

What enzyme eats the poly A tail?

A

poly A nuclease

68
Q

What happens if there is only part mRNA for translation?

A

-do not want to synthesize part proteins so mRNA is degraded

69
Q

What is transferrin and what does it bind?

A
  • transport protein for iron

- binds to transferrin receptor which is found in cells

70
Q

What regulates the synthesis of transferrin receptors in the cell? How?

A
  • regulated in response to levels of iron in the cell

- if cell levels of iron are high, does not need more receptor, mRNA is degraded

71
Q

What sequence regulates mRNA stability in response to iron? What does it consist of?

A
  • 3’ UTR sequence of the transferrin receptor mRNA called IRE
  • consists of a hairpin loop in the mRNA
72
Q

What happens when iron levels are low? high?

A

low- the hairpin loop is bound and stabilized by a protein called IRE-BP (cyclic aconitase), makes the whole mRNA stable and allows more transferrin receptor to be made

high- Fe binds the IRE-BP and changes its conformation so that it is released from the mRNA, hairpin loop is not stabilized and mRNA is degraded, so less transferrin receptor is made

73
Q

The exonuclease proteins that shorten the poly A tail in the cytosol compete directly with what?

A

proteins involved in translational initiation for binding to the poly A tail and 5’ cap

74
Q

Factors that decrease translational efficiency of an mRNA have what effect on mRNA degradation?

A

increase degradation

75
Q

Factors that increase translational efficiency of an mRNA have what effect on mRNA degradation?

A

decrease degradation

-actively translated mRNA are more stable and get degraded slower

76
Q

What is nonsense mediated decay?

A
  • RNA surveillance
  • process by which some abnormal transcripts(nonsense codons, unspliced introns, extended 3’ UTRs-looks like early stop codon) are rapidly degraded without being deadenylated first
77
Q

Describe the process of nonsense mediated decay?

A
  1. nuclear surveillance proteins mark exon-exon boundaries on the mature mRNA prior to export to the cytosol, test round of translation is done near the nuclear envelope
  2. if an in-frame stop codon is found before the last exon-exon border, the mRNA is quickly degraded
78
Q

What are miRNAs? What are they processed by? What do they combine with?

A

small single stranded RNAs that are processed by Dicer and combine with Argonaute proteins in cytoplasm to form RISC complexes

79
Q

What does the RISC complex bind to? How? What does it do?

A
  • Risc complex binds to the 3’ UTR of target mRNA by complementary base pairing between the miRNA and the mRNA
  • this inhibits protein synthesis
80
Q

T/F

miRNAs can bind to sequences that are not completely complementary.

A

true

81
Q

How many genes can miRNA regulate?

A
  • can regulate multiple genes

- estimated 2/3 of protein encoding genes in genome are regulated by miRNA

82
Q

How many miRNAs can bind an mRNA? What is the purpose?

A
  • each mRNA can be bound by multiple miRNAs
  • this allows for fine tuned regulation by multiple miRNAs, since expression of each miRNA can be regulated independently- combinatorial control, net effect
83
Q

What happens to mRNAs with two or more miRNA containing RISC complexes bound?

A

they are sequestered in P bodies in the cytoplasm, which contain no ribosomes or translation factors, so targeted mRNA is not translated and is degraded

84
Q

What happens when the complementarity between miRNA and mRNA is high? low?

A
  • high- mRNA is degraded quickly
  • low- stays sequestered in P bodies for a longer time, eventually degraded

-either way less protein is made

85
Q

How can miRNAs function as tumor suppressors? oncogenes? What is their expression influenced by?

A

suppressors- turns off expression, more cancer

oncogenes- turns on expression, more cancer

-expression influenced by epigenetic changes in tumor cells such as DNA methylation and formation of heterochromatin limit expression

86
Q

How can miRNAs affect chromatin structure?

A

by targeting chromatin remodeling proteins and methyltransferases

87
Q

Inhibition requires how many miRNAs?

A

at least two, combinatorial control= net effect of the miRNAs

88
Q

What is the benefit of miRNA functioning as epigenetic effectors when passed to daughter cells?

A

helps maintain cell memory

89
Q

What is RNA editing? How many genes does it affect? Where does it take place? What does it require?

A
  • alters sequence of an mRNA after transcription
  • rare mechanism- may affect about 1600 genes
  • takes place in nucleus
  • requires deaminase which are expressed in cell or tissue specific manner
90
Q

What do deaminase enzymes do? ApoB48?

A
  • they change a ribonucleotide, which changes a codon in mRNA, which causes a different amino acid to be incorporated into the protein, changing it properties
  • ApoB48- deaminase creates a stop codon and results in production of a shorter protein
91
Q

Deamination of A to inosine in RNA editing? When is this important? What could altered editing patterns cause?

A
  • hypoxanthine with sugar
  • base pairs with C instead of U, changes the codon-anticodon pairing, and the amino acid
  • important in brain receptors and ion channels
  • altered editing associated with inflammation, epilepsy, depression, gliomas, ALS
92
Q

What does the deamination of C to U cause in RNA editing?

A
  • creation of stop codon

- important for ApoB protein

93
Q

Apolipoprotein B gene with no editing vs with editing?

A

no edit (B100)- CAA stays same, binds to LDL receptor, protein made in liver, transports endogenous fatty acids in blood

with edit (B48)- CAA turns to UAA, lacks LDL, protein made in intestine, chylomicrons transports dietary fatty acids

94
Q

Difference in translational regulation compared to transcriptional regulation? Translational rate limiting step?

A
  • effects occur more quickly than transcriptional
  • short term regulation of protein levels
  • important form of developmental regulation
  • especially important in enucleated cells (RBC)
  • rate limiting- initiation, most regulated step
95
Q

What are three ways to regulate translation?

A
  1. accessibility of 5’ cap
  2. phosphorylation of eIF2
  3. repression mediated by sequences in 3’ UTR
96
Q

How to make the 5’ cap less accessible to cap binding protein? Example-ferritin?

A
  • proteins that stabilize structures in 5’ UTR can repress translation by making the cap less accessible
  • translation of ferritin (storage protein for iron) and ALA synthase 2(enzyme that catalyzes rate limiting step of heme synthesis in erythrocytes) regulated in response to iron levels
97
Q

What happens when there is high iron content? low iron?

A
  • more ferritin is made to store in cells

- less ferritin is made

98
Q

Reactivation of eIF2-GDP can be inhibited by what? Result?

A
  • phosphorylation
  • results in inhibition of most translation in that cell, especially initiation of translation and protein synthesis from most mRNAs
99
Q

How is eIF-2-GTP normally created?

A

eIF2B binds the inactive eIF-2-GDP and causes it to release the GDP. GTP can then bind eIF2 to create the active form

100
Q

How does the phosphorylation of eIF-2-GDP prevent the formation of eIF-2-GTP?

A

phosphorylation of eIF-2-GDP causes it to form a stable complex with eIF2B. This hides eIF2B, present in limited amounts, and prevents the formation of the active complex

101
Q

In erythrocytes, what prevents the phosphorylation of eIF-2-GDP? How? Result?

A

heme

  • by binding to and inactivating heme kinase
  • results in continued protein synthesis when heme levels are high, but decreased protein synthesis when heme levels are low
102
Q

What do eIF2 kinases do? Kinds of stress?

A
  • 4 different kinases inhibit translation in response to stress in mammalian cells
  • amino acid starvation, ER stress, double stranded RNA
103
Q

How do sequences in the 3’ UTR regulate translation?

A
  • factors that binds sequences in the 3’ UTR can interact with cap binding complex or the small ribosomal subunit
  • mRNA may be directed to certain regions of the cell where translation is more likely to occur
  • in most cases, protein binding to the 3’ UTR represses translation
104
Q

What are 5 post translational regulations?

A
  1. protein folding
  2. protein sorting
  3. glycosylation
  4. alternative cleavage
  5. protein degradation
105
Q

Why are proteins modified post translationally?

A
  • prepare them for their function
  • target them to the correct cell location
  • regulate biological activity
106
Q

Where can proteins be synthesized?

A
  • free ribosomes in the cytosol

- membranous ribosomes bound to the ER

107
Q

Proteins made on free ribosomes are released where? Then where can they go (default)?

A
  • directly into the cytosol
  • localized to nucleus or mitochondria if signals present
  • default-no signal, stay in cytosol
108
Q

Where do proteins made on the rough ER go? Default?

A
  • pass into the ER as they’re being synthesized (co translational translocation)
  • some are deposited in the lumen of the ER (enzymes involved in lipid and steroid synthesis, drug and chemical metabolism)
  • some are retained in the golgi apparatus
  • some are incorporated into plasma membrane
  • some are sent to lysosomes
  • default-no signal, secretion
109
Q

What targets proteins for translation on the ER? What cleaves it?

A
  • signal sequence- short amino acid sequence at the N terminus that directs the protein into the lumen of the ER
  • leader sequence is cleaved by signal peptidase before translation is complete
110
Q

What is the process that guides the signal peptide to the ER?

A
  1. a signal recognition particle (SRP) binds the signal peptide in the cytosol and brings the ribosome and nascent peptide to the ER, ribosome pauses
  2. an SRP receptor on the ER membrane binds the SRP-ribosome complex
  3. a ribosome receptor stabilizes the binding while a protein translator transfers the growing polypeptide chain across the ER membrane
111
Q

Where are chaperones and chaperonins located? Functions? what increases their function?

A
  • in ER, cytoplasm, mitochondria
  • assist proper folding of newly synthesized or translocating proteins
  • prevent improper aggregation with other proteins
  • synthesis, activity increased by various types of cell stress
  • high activity when exposed to heat
112
Q

What are the consequences of misfolding proteins?

A
  • non functional proteins, loss of normal function
  • aggregate with other proteins and interfere with their activity
  • quality control mechanisms may be overwhelmed and cause more protein misfolding
  • multiple pathways may be affected
  • toxic gain of function
  • usually degraded
  • many diseases are caused by failure to fold proteins properly
113
Q

What is the unfolded protein response (UPR)? What does it do? Translation increase or decrease? What happens if stress continues?

A
  • ER stress response
  • stress sensors in the ER membrane detect accumulated misfolded proteins
  • decrease in translation of most mRNAs not involved in the problem
  • increased levels of chaperones and proteins involved in degradation of misfolded proteins
  • if stress continues, cell undergoes apoptosis
114
Q

How does the process of UPR work?

A
  • three sensors detect misfolded proteins
  • phosphorylation of eIF2 inactivates translation of most proteins that enter the ER
  • transcriptional response increase levels of gene expression of chaperones which help fold proteins correctly
  • dephosphorylation brings normal translation of other proteins
  • if this process doesn’t work, cell death (apoptosis)
115
Q

What is the purpose of N linked glycosylation in the ER?

A
  • helps protein folding
  • stability
  • aids in activity of protein
116
Q

Where does the first glycosylation occur in the ER? Then where does the protein go?

A
  • while the protein is still attached to the membrane of the ER
  • groups of sugars are formed on a lipid in the membrane, then transferred in bulk to the nascent protein (asparagine usually) in the lumen of the ER
  • sugars are modified and rearranged as the protein passes through the ER and Golgi
117
Q

What modifications can happen during protein processing and trafficking in the golgi apparatus? What are these processes related to?

A
  • further glycosylation, phosphorylation, sulfation

- these modifications are related to the localization and function of the mature protein

118
Q

How are lysosomal proteins sorted? How are pre lysosomes formed?

A
  • by virtue of the phosphate group added to mannose (mannose 6 phosphate)
  • mannose 6 phosphate is recognized by specific receptors in the trans golgi that retain lysosomal proteins in vesicles that bud off to form pre lysosomes
119
Q

What is I cell disease? Result?

A
  • patients are deficient in one of the enzymes involved in phosphorylating mannose on acid hydrolyses normally directed to lysosomes
  • result- protein is secreted instead of being localized in lysosomes, leading to functional deficiency in these proteins
  • hydrolases don’t function
  • skeletal abnormalities
120
Q

Role of Cis and Trans Golgi?

A

cis- receives vesicles from ER

trans- sends vesicles to different targets

121
Q

Where are membrane glycoproteins transported to?

A

basolateral membrane

122
Q

Where are many soluble proteins (all cells) secreted? Is it regulated? How are the proteins packaged?

A
  • by a rapid and continuous constitutive secretory pathway that works in all cells and sends proteins to the plasma membrane unless there are specific signals for another destination
  • not regulated
  • proteins combine with newly synthesized lipids to make transport vesicles that fuse with the cell membrane
123
Q

What type cells undergo a regulatory secretory pathway? How does this path work?

A
  • specialized secretory cells
  • proteins have a sorting signal that directs them into and segregates them into secretory granules
  • the granules wait near the plasma membrane until the cell receives a signal to secrete
124
Q

What do most secreted and some plasma membrane proteins undergo while in secretory or transport vesicles?

A

post golgi proteolytic cleavage

125
Q

What does proteolytic cleavage activate?

A

many polypeptide hormones, neuropeptides, and secreted hydrolytic enzymes that synthesized as inactive precursors

126
Q

Where does cleavage begin? Where does it continue?

A

begins in the trans golgi and continues in secretory vesicles and sometimes even in extracellular fluid after secretion

127
Q

In complex cases, how can a single protein be cleaved?

A

in various ways to produce different proteins in different cell types

128
Q

Where are nonfunctional protein from the ER degraded?

A

-proteasomes in the cytosol, abundant

129
Q

When is it necessary to degrade proteins?

A
  • nonfunctional, unable to fold or assemble properly
  • they are at the end of their lifespan
  • their concentration must change rapidly (cyclins)
  • they are foreign proteins taken up by the cell
130
Q

What are proteasomes? What are they dependent upon?Function? Structure?

A
  • ATP dependent proteases
  • large cytoplasmic complex containing proteolytic enzymes
  • degrades proteins to small peptides
  • structure protects the cell from inappropriate proteolysis
131
Q

Proteins are targeted for degradation in proteasome by what?

A

covalent attachment of multiple copies of a small protein called ubiquitin

132
Q

How is ubiquitin added to proteasomes? How are the degradation signals exposed? What complex adds ubiquitin? How many of these complexes does each cell have? How do you regulate degradation of protein?

A
  • it is added by ubiquitin conjugating enzymes that recognize degradation recognition signals on the proteins
  • exposed by denaturation, improper folding, chemical damage
  • ubiquitin ligase adds it to protein E2-E3
  • each cell has many ubiquitin ligases that recognize distinct degradation signals- polyubiquitination
  • can be regulated by by regulating the activation of the ubiquitin ligase or by regulating the availability of the degradation signal
133
Q

TET2 mutation significance?

A

mutated or deleted in certain types of leukemia

MBM (24 decks)

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