In 1970 Gunter Blobel discovered proteins had signal sequences which directs where in the cell they go.
This post is looking at the HLAs (t-cell mailboxes) as proteins with location sequences.
Note that all HLA-Ds are made by APCs and the NK cell would have popped infected cells open and any virus in the cytosol could be seen by APC (antigen presenting cells) Therefore we are only looking at HLA-A, HLA-B, and HLA-C for locations
Based on the viruses involved with each HLA (earlier post) we have this pattern:
HLA-As, HLA-Bs, and HLA-Cs have the hydrophobic sequence sending them to the Endoplasmic Reticulum. Does the HLA-C never leave? The HLA-Ds do not have this sequence.
Where and what is the sequence in HLA-C for holding proteins in the ER? No KDEL code but the TAP-1 and TAP-2 proteins' genes are on chromosome 6 after HLA-A before HLA-C.
HLA-C strongly binds to TAP and are held at the endoplasmic reticulum
https://www.ncbi.nlm.nih.gov/pubmed/9551969/
TAP : transporter associated with antigen processing (an endoplasmic reticulum protein)
https://books.google.com/books?id=vdZlqAJBDtoC&pg=PA135&lpg=PA135&dq=chromosome+6+endoplasmic+reticulum+proteins&source=bl&ots=84aBlFqKcC&sig=oac7VKo0tSu2eQvNCKhv59mUGpE&hl=en&sa=X&ved=0ahUKEwiq_Kq8iIXQAhXGyVQKHRDSA_kQ6AEIOzAH#v=onepage&q=chromosome%206%20endoplasmic%20reticulum%20proteins&f=false
HLA-A and the nucleus
HLA-A has been found to move to the nucleus..(.but this paper believed it was the nef protein that made it move)
https://www.ncbi.nlm.nih.gov/pubmed/12414957
HLA-As should have a very basic internal lysine loop that will get into the Nucleus from the ER.
I have not found this NLS, nuclear leader sequence, yet. I entered the HLA-A1 gene
Could this be in the middle because HLAs are signal peptides? (that have to move to the plasma membrane having bound something)
most nuclear sequences have lysine (k) and arginine (R) sequences
http://www.jbc.org/content/284/1/478/F2.expansion.html
Since HLA-A, HLA-B, and HLA-C all have RRKSS (301-350 ) but HLA-D, which are found in the cytosol don't have this sequence, I am thinking that this RRKSS is the nuclear sequence. Logically important sequences are conserved when possible but removed if necessary.
I have also found this nuclear membrane protein syne-1 with HLA-A.
Are the genes of proteins from the same cellular area stored together on chromosome 6?
SCA heredity spinocerebellear ataxia and HLA
http://onlinelibrary.wiley.com/doi/10.1002/ana.410230609/full
http://onlinelibrary.wiley.com/doi/10.1111/j.1600-0404.1992.tb04041.x/full
http://onlinelibrary.wiley.com/doi/10.1111/j.1399-0039.1992.tb02101.x/abstract;jsessionid=900F1E2A692F3CEF47264FFA7735A276.f04t01
syne-1 and autosomal recessive cerebellar ataxia (beauce)
https://www.ncbi.nlm.nih.gov/pubmed/23959263/
Syne-1 is on chromosome 6.
Is this nuclear membrane protein, syne-1, next to HLA-A which I suspect is translocated to the nucleus?
HLA-Ds will not have the hydrophobic ER sequence or the nuclear sequence if they are located in the cytosol.
HLA-B and the mitochondria
HLA-B's sequence
HLA-B35 N-terminal motifs are canonical sequences
http://www.jimmunol.org/content/181/7/4874.full.pdf
The mitochondrial entry sequences are hydroxylated proteins; the water loving -OH containing proteins.
Looking at the "dvslta" end of the protein: serine and threonine are already hydroxyl proteins.
The alanine when hydroxylated becomes serine and the valine becomes threonine.
Creating a strong hydroxylated sequence ts-l-ts which could bring the HLA-B protein into the mitochondria.
The HLA-B has a close association with, is linked to, steroid 21-hydroxylase
https://www.ncbi.nlm.nih.gov/pubmed/3009365
http://www.jstor.org/stable/24663?seq=1#page_scan_tab_contents
Does the steroid 21-hydroxylase act on the HLA-B which then allows it to enter the mitochondria? Are these genes together for a reason?
Ran HLA-B sequence and it didn't find a mitochondrial sequence just "secretion pathway sequence"
Could my prediction be wrong?
C-----N protein
The C terminal end is where the HLAs are embedded in the membrane?
Which leads me to ponder if the HLAs are facing inward until they bind an antigen. Does the protein's conformation change when HLAs have bound an antigen ? Does this protein shape change then lead to glycosylation ? Sugars being added which then would cause the HLA protein to be moved to the outside of the cellular membrane?
polysaccharides appear to be involved with Antigen presenting cell's HLAs
https://www.ncbi.nlm.nih.gov/pubmed/15163414/
Note that the basic rule of proteins inserted in the plasma membrane is no sugars in the cytosol. That piece of the protein goes outside of the cell. Hence a protein can be weaved back and forth on a membrane based on glycosylation.
This post is looking at the HLAs (t-cell mailboxes) as proteins with location sequences.
Note that all HLA-Ds are made by APCs and the NK cell would have popped infected cells open and any virus in the cytosol could be seen by APC (antigen presenting cells) Therefore we are only looking at HLA-A, HLA-B, and HLA-C for locations
Based on the viruses involved with each HLA (earlier post) we have this pattern:
HLA-A the nucleus
HLA-B the mitochondria
HLA-C the endoplasmic reticulum
HLA-DR the cytosol (encapsulated virus)
HLA-DQ the cytosol (not an encapsulated virus)
HLA-DP the plasma membrane/ endocytosis
The question is: do the HLAs have the appropriate signal sequences for these locations?
HLA-C and the endoplasmic reticulumThe question is: do the HLAs have the appropriate signal sequences for these locations?
HLA-As, HLA-Bs, and HLA-Cs have the hydrophobic sequence sending them to the Endoplasmic Reticulum. Does the HLA-C never leave? The HLA-Ds do not have this sequence.
Where and what is the sequence in HLA-C for holding proteins in the ER? No KDEL code but the TAP-1 and TAP-2 proteins' genes are on chromosome 6 after HLA-A before HLA-C.
HLA-C strongly binds to TAP and are held at the endoplasmic reticulum
https://www.ncbi.nlm.nih.gov/pubmed/9551969/
TAP : transporter associated with antigen processing (an endoplasmic reticulum protein)
https://books.google.com/books?id=vdZlqAJBDtoC&pg=PA135&lpg=PA135&dq=chromosome+6+endoplasmic+reticulum+proteins&source=bl&ots=84aBlFqKcC&sig=oac7VKo0tSu2eQvNCKhv59mUGpE&hl=en&sa=X&ved=0ahUKEwiq_Kq8iIXQAhXGyVQKHRDSA_kQ6AEIOzAH#v=onepage&q=chromosome%206%20endoplasmic%20reticulum%20proteins&f=false
HLA-A and the nucleus
HLA-A has been found to move to the nucleus..(.but this paper believed it was the nef protein that made it move)
https://www.ncbi.nlm.nih.gov/pubmed/12414957
HLA-As should have a very basic internal lysine loop that will get into the Nucleus from the ER.
I have not found this NLS, nuclear leader sequence, yet. I entered the HLA-A1 gene
The NucPred score for your sequence is 0.44 (see score help below)
1 MAVMAPRTLLLLLSGALALTQTWAGSHSMRYFFTSVSRPGRGEPRFIAVG 50 51 YVDDTQFVRFDSDAASQKMEPRAPWIEQEGPEYWDQETRNMKAHSQTDRA 100 101 NLGTLRGYYNQSEDGSHTIQIMYGCDVGPDGRFLRGYRQDAYDGKDYIAL 150 151 NEDLRSWTAADMAAQITKRKWEAVHAAEQRRVYLEGRCVDGLRRYLENGK 200 201 ETLQRTDPPKTHMTHHPISDHEATLRCWALGFYPAEITLTWQRDGEDQTQ 250 251 DTELVETRPAGDGTFQKWAAVVVPSGEEQRYTCHVQHEGLPKPLTLRWEL 300 301 SSQPTIPIVGIIAGLVLLGAVITGAVVAAVMWRRKSSDRKGGSYTQAASS 350 351 DSAQGSDVSLTACKV 365
Positively and negatively influencing subsequences are coloured according to the following scale:
(non-nuclear) negative ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| positive (nuclear)
Could this be in the middle because HLAs are signal peptides? (that have to move to the plasma membrane having bound something)
most nuclear sequences have lysine (k) and arginine (R) sequences
http://www.jbc.org/content/284/1/478/F2.expansion.html
Since HLA-A, HLA-B, and HLA-C all have RRKSS (301-350 ) but HLA-D, which are found in the cytosol don't have this sequence, I am thinking that this RRKSS is the nuclear sequence. Logically important sequences are conserved when possible but removed if necessary.
I have also found this nuclear membrane protein syne-1 with HLA-A.
Are the genes of proteins from the same cellular area stored together on chromosome 6?
SCA heredity spinocerebellear ataxia and HLA
http://onlinelibrary.wiley.com/doi/10.1002/ana.410230609/full
http://onlinelibrary.wiley.com/doi/10.1111/j.1600-0404.1992.tb04041.x/full
http://onlinelibrary.wiley.com/doi/10.1111/j.1399-0039.1992.tb02101.x/abstract;jsessionid=900F1E2A692F3CEF47264FFA7735A276.f04t01
syne-1 and autosomal recessive cerebellar ataxia (beauce)
https://www.ncbi.nlm.nih.gov/pubmed/23959263/
Syne-1 is on chromosome 6.
Is this nuclear membrane protein, syne-1, next to HLA-A which I suspect is translocated to the nucleus?
HLA-B and the mitochondria
HLA-B's sequence
mlvmaprtvl lllsaalalt etwagshsmr yfytsvsrpg rgeprfisvg yvddtqfvrf 61 dsdaaspree prapwieqeg peywdrntqi ykaqaqtdre slrnlrgyyn qseagshtlq 121 smygcdvgpd grllrghdqy aydgkdyial nedlrswtaa dtaaqitqrk weaareaeqr 181 raylegecve wlrrylengk dkleradppk thvthhpisd heatlrcwal gfypaeitlt 241 wqrdgedqtq dtelvetrpa gdrtfqkwaa vvvpsgeeqr ytchvqhegl pkpltlrwep 301 ssqstvpivg ivaglavlav vvigavvaav mcrrkssggk ggsysqaacs dsaqgsdvsl 361 ta
HLA-B35 N-terminal motifs are canonical sequences
http://www.jimmunol.org/content/181/7/4874.full.pdf
The mitochondrial entry sequences are hydroxylated proteins; the water loving -OH containing proteins.
Looking at the "dvslta" end of the protein: serine and threonine are already hydroxyl proteins.
The alanine when hydroxylated becomes serine and the valine becomes threonine.
Creating a strong hydroxylated sequence ts-l-ts which could bring the HLA-B protein into the mitochondria.
The HLA-B has a close association with, is linked to, steroid 21-hydroxylase
https://www.ncbi.nlm.nih.gov/pubmed/3009365
http://www.jstor.org/stable/24663?seq=1#page_scan_tab_contents
Does the steroid 21-hydroxylase act on the HLA-B which then allows it to enter the mitochondria? Are these genes together for a reason?
Ran HLA-B sequence and it didn't find a mitochondrial sequence just "secretion pathway sequence"
Name Len mTP SP other Loc RC ---------------------------------------------------------------------- Sequence 362 0.054 0.911 0.030 S 1 ---------------------------------------------------------------------- cutoff 0.000 0.000 0.000
Could my prediction be wrong?
C-----N protein
The C terminal end is where the HLAs are embedded in the membrane?
Which leads me to ponder if the HLAs are facing inward until they bind an antigen. Does the protein's conformation change when HLAs have bound an antigen ? Does this protein shape change then lead to glycosylation ? Sugars being added which then would cause the HLA protein to be moved to the outside of the cellular membrane?
polysaccharides appear to be involved with Antigen presenting cell's HLAs
https://www.ncbi.nlm.nih.gov/pubmed/15163414/
Note that the basic rule of proteins inserted in the plasma membrane is no sugars in the cytosol. That piece of the protein goes outside of the cell. Hence a protein can be weaved back and forth on a membrane based on glycosylation.
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