Proteopathic diseases and amelogensis imperfecta Flashcards
what is the definition of proteopathies
class of diseases where proteins structure becomes abnormal and disrupts the function of cells, tissues, and organs of the body
what usually happens to the protein structure
fail to fold into their normal configuration
why is the misfiled state dangerous
the proteins can become toxic and lose their normal function
what can lead to misfoldings of proteins
mutations and this can also lead to abnormal aggregation
what is an example of proteopathy
alzheimers disease- which occurs due to an accumulation of misfiled protein in the brain which forms plaques
what is the major aggregating protein in some forms of amelogenesis imperfecta
amelogenin
what are the stages of protein synthesis
- begins when a gene on DNA produces mRNA
- the mRNA leaves via nuclear pore and attaches to a ribosome in the cytoplasm or on RER
- when proteins are produced via transcription and translation they are released into the cytoplasm
- protein is threaded into the tubes of the ER where it starts to fold into 3D shape
- the proteins are modified here and bud off in a transport vesicle
- the transport vesicle moves the protein to the golgi apparatus on the receiving face of the golgi
- in the cisternae of the golgi modification and packing occurs and moves towards the shipping face
- on the shipping face side - one type can become a lysosome and contain digestive enzymes
- transport of the vesicle and fuses with the membrane and exocytosis of the protein occurs
what are the types of vesicles that can be produced
transport vesicle
membrane renewal vesicle-
secreting vesicle- secrete products by fusing with the membrane and removing products by exocytosis
what do membrane renewal vesicles do
add new lipids and proteins to reform the membrane
what do secreting vesicles do
secrete products by fusing with the membrane and removing products by exocytosis
what issues can happen in the ER
misfolded proteins can accumulate in the space and stall this causes stress in the cell and can cause apoptosis
how is a protein identified as a secretory protein
the protein has sequence a N terminus which is called the signal peptide
what is the signal peptide
it is a short peptide located on the N terminus of the amino acid( at the beginning) which identifies the protein is secretory
what are the stages of translocation of proteins to the ER of CO translational translocation
- the protein has sequence a N terminus which is called the signal peptide- this is identified
- the peptide is inserted into a translocation channel in the ER membrane and the process continues and the protein is translocated into the ER
what are the stages of POST translational translocation
- protein translated first completely in cytoplasm
2. because of the signal recognition sequence gets translocated into the ER
what is protein folding directed by
chaperones
what is an example of a chaperone
BIP
what are chaperones
proteins that accompany proteins to other areas and asssit with correct folding
what reaction is protein folding
a dynamic process which takes time
what type of structures form first in protein folding
local secondary structures such as a helix or B pleated sheet
what forms after local secondary structures
longer range interactions
what problems can you encounter if you have a point mutation
will change the primary structure—-> then the secondary and result in the misfolded protein—-> this can result in the protein aggregating and fibres accumulating in the ER—-> leading to ER stress and then disease eg Alzheimers
what can happen in the ER when a protein is misfolded
protein aggregation,
inclusion bodies and fibres accumulate in the ER
what can happen if we have a protein with a neutral charge that undergoes a point mutation and becomes charged
the protein will have a charge and form interactions leading to irreversible protein damage by protein misfolding
what protein accumulates in the brain in Alzheimers
TAU protein accumulates and creates plaques which cause lesions
what is another way you can get ER stress
the 3D structure forms correctly and gets additional groups added eg phosphate group which is added in the wrong place adds a NEGATIVE charge which leads to different structure
what is additional phosphate groups being added to proteins called
hyperphosphorylation
what percentage of proteins misfold or are incorrectly processed under normal circumstances
10-30%
Why don’t we constantly get ER stress and proteopathic disease
Cells employ quality control mechanisms to identify faulty proteins and take steps to relieve the ER stress – the so called “unfolded protein response” (UPR)
why might some misfolded proteins still be present
as the quality controlled mechanisms can miss things or become overwhelmed
what are the steps of the unfolded protein response
- in the ER newly synthesised proteins must be correctly folded so they can function or be transported
- proteins that have failed to correctly fold are initially retained in the ER BY BINDING TO CHAPERONE PROTEINS
- the chaperones prevent aggregation of misfolded proteins or unfolded and help steer them to be folded correctly
- if proteins fail to be correctly folded they are transported by chaperones and other molecules to transporters which allow them to pass into the cytosol and eventually degrade
- if the ER capacity to fold or degrade is overwhelmed misfolded proteins accumulate in there lumen and this triggers the UPR which activates genes which increase the folding capacity of the ER and can inhibit protein synthesis
- the UPR has three pathways- IRE1, PERK,ATF6
what is the IRE1
IRE1- transmembrane protein kinase
what is the pathway of IRE1
1.misfolded proteins in the ER lumen trigger IRE1 to oligermerise and the adjacent kinase domains on another IRE1 phosphorylase the RNase is activated.
2.it can now cleave specifics cytosolic pre mRNA molecule at two points releasing the intron
3. Exons joined by RNA ligase
4. the spliced MRNA is translated into an activate transcription regulatory protein 1
5. enters the nucleus
and activates target genes which expand the ER, increase protein folding capacity, enhance degradation of misfolded proteins
what domains does IRE1 have
two catalytic domains on its cytosolic side with a kinase domain and ribonuclease domain
what is PERK activated by
accumulation of misfolded proteins
what are the three UPR PATHWAYS
IRE1
PERK
ATF6
what is PERK
A transmembrane protein kinase
what are the stages of the UPR regarding PERK
- upon activation the PERK phosphorylates ITSELF
- then phosphorylates a translation initiation factor which INACTIVATING IT
- two consequences: inhibits overall protein synthesis, decreases the load of protein folding. increases the production of transcription regulator protein 2
- in the nucleus, the transcription regulator protein activates target genes
what is ATF6
contains a transcription regulator which will be transported to the nucleus
what is the pathway for ATF6
- accumulation of misfolded proteins triggers ATF6 to be transported from the ER lumen to the golgi apparatus
- In the golgi membrane, ATF6 encounters proteases which cleaves of cytosolic domain which allows an active and free transcription regulatory protein 3
- migrates into the nucleus and helps with transcription of target genes
does the UPR differ in different cell types
yes it allows cells to tailor the UPR to the requirements of different cell types
what is BIP
a chaperone which stands for binding immunoglobulin protein
describe BIP
HSP70 molecular chaperone
what does BIP control
transmembrane sensors
what is BIP also known as
GRP78
what are factors that are pro survival
ERAD
BIP
activation of genes to increase protein folding capacity
chaperones
what is against cell survival
APOPTOSIS
what does the UPR ACT AS
a binary switch between cell survival or cell apoptosis when ER stress is present
what does mild stress or short term stress induce
a regulated UPR in which survival effectors outweigh death leading to survival of the cell
what does long term stress lead to
the UPR becoming hyperactive and then leading to apoptosis and disease
