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A hairpin turn in a HIV-gag–derived peptide---Prion?

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posted on Feb, 28 2005 @ 06:23 AM
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Figure 1.Alignment of HLA-DR crystal structure exhibiting ordered peptide density beyond the P10 residue. Complexes were aligned by least-squares fitting of α1 and β1 domains of the MHC protein. Peptides are shown as Cα traces. DR1/TPI is red (PDB ID code 1KLU), DR2a/MBP is blue (PDB ID code 1FV1), DR3/CLIP is magenta (PDB ID code 1A6A), DR1/Ha is cyan (PDB ID code 1DLH), DR2a/EBV is gray (PDB ID code 1H15), and DR4/collagen is orange (PDB ID code 2SEB).




Figure 2.The Gag[PP16] hairpin turns orients important C-terminal residues in position to interact with the TCR. Side view of surface of HLA-DR1 with the Gag[PP16] peptide shown as a stick model. Peptide side chains essential for T-cell activation are red and those important for peptide binding to HLA-DR1 are blue. Met(P4) is in orange, it affects both MHC peptide binding and T-cell activation


"T-cell receptors (TCRs) recognize peptide antigens bound to class II Major Histocompatibility Complex (MHC) proteins—molecules that transport and present the antigens to the T-cells, thus activating the immune system response. The receptors contact the antigen residues within or immediately flanking the seven-to-nine-residue sequence accommodated by the MHC-peptide binding groove. We identified a HIV-Gag-specific T-cell clone that requires an unusually long peptide for activation. The crystal structure of the HIV-gag peptide bound to an MHC protein known as HLA-DR1 shows that the peptide binds in an unexpected conformation, with its C-terminal region making a hairpin turn that bends back over the groove. The residues at the C-terminus are critical for T-cell recognition, and disrupting the hairpin cancels the immune response. The results suggest a new mode of MHC-peptide-TCR interaction.

www.nsls.bnl.gov...

This is a very intresting find, the key issue in this data is the "hairpin" shaped "protien". The article does not say this but the misshaped protein could be also classified as a prion............More evidence of prions in HIV.........

[edit on 28-2-2005 by DrHoracid]




posted on Feb, 28 2005 @ 10:45 AM
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Hmmm. Very interesting.

...For those who don't know: Proteins are the building blocks of life - there are millions of different proteins and the body creates each one on order, tailored to do a very specific job. Proteins build cells by using a lock and key principle - proteins are 'coded' genetically - every protein key fits a specific protein lock in a particular way, first to build cells, then tissues, organs and other body parts. Kind of like a biological puzzle, where the pieces are created exactly and only when they're needed.

Prions are "misfolded proteins" - they muck up the works because they weasel in where they don't belong, hijack the protein-building and cell-building processes, and take over the works by causing mutations first in the proteins, and then down the line.


FYI - even before prions were identified officially, their role in mucking up the immune system was well known. ...One of the main difficulties was that there were so many different ways that the muck up occurred, no one could sort it out. .

..The big hold-up was that genetic dogma said only genes could determine protein production and formation. To even suggest anything else was tantamount to heresy. ...But wrong. Prions can and do determine protein formation - they hijack gene function and often, cause genetic mutations.

...Now it's known that prions adapt to new cells and particles by mutating and shape-shifting - into whatever form or "key" will fit a particular lock. ...Researchers keep finding new and different infected proteins - enzymes, proteases, kineases and in this case, a peptide. ...and the list keeps growing.


The "HLA-DR" system was identified very early on as the main pathway that prions use to access the immune system - and it's how they 'get in' to cause genetic mutations. ...Biologists, nephrologists and transplant doctors had world conferences in the early 1980's about HLA-DRw6


A few references from one of my HLA-DR files:

The genetics of the HLA system. McDevitt HO. J Rheumatol Suppl. 1983 Nov;10:50-3. PMID: 6319697

Reanalysis of the HLA-DRw6 complex. Schreuder GM, Parlevliet J, Termijtelen A, van Rood JJ. Tissue Antigens. 1983 Jan;21(1):62-74. PMID: 6601316

Monoclonal antibody identifies a new Ia-like (p29,34) polymorphic system linked to the HLA-D/DR region. Nature. 1981 Apr 16;290(5807):591-3. Nadler LM, Stashenko P, Hardy R, Tomaselli KJ, Yunis EJ, Schlossman SF, Pesando JM. PMID: 6163992

An HLA-D region restriction fragment length polymorphism associated with celiac disease. J Exp Med. 1986 Jul 1;164(1):333-8. Howell MD, Austin RK, Kelleher D, Nepom GT, Kagnoff MF. PMID: 3014038

DNA polymorphism of HLA class II genes in systemic lupus erythematosus. Tissue Antigens. 1994 Jan;43(1):34-7. Cowland JB, Andersen V, Halberg P, Morling N. Institute of Forensic Genetics, University of Copenhagen, Denmark. PMID: 7912858

HLA-DO polymorphism associated with resistance to type I diabetes detected with monoclonal antibodies, isoelectric point differences, and restriction fragment length polymorphism. J Exp Med. 1986 Sep 1;164(3):938-43. Schreuder GM, Tilanus MG, Bontrop RE, Bruining GJ, Giphart MJ, van Rood JJ, de Vries RR. PMID: 3462303

The new HLA-DRw6- and 8- associated HLA-Dw HAG specificity defined by homozygous typing cell 9W 1802. Analysis with primed lymphocyte typing clones. Tissue Antigens. 1984 Nov;24(5):292-301. Pawelec G, Muller C, Rehbein A, Balko I, Schunter F, Wernet P. PMID: 6085195

Different specificities of an HLA-DRw6 haplotype detected by alloreactive T lymphocytes. Hum Immunol. 1984 Dec;11(4):193-205. Myers LK, Ball EJ, Stastny P. PMID: 6210279

HLA-A, B, DR, and DQ antigens in black patients with severe chronic rheumatic heart disease. Circulation. 1987 Aug;76(2):259-61. Maharaj B, Hammond MG, Appadoo B, Leary WP, Pudifin DJ. PMID: 3475188

Analysis of the sheep MHC using HLA class I, II, and C4 cDNA probes. Immunogenetics. 1985;22(4):349-58. Chardon P, Kirszenbaum M, Cullen PR, Geffrotin C, Auffray C, Strominger JL, Cohen D, Vaiman M. PMID: 2997030

Human influenza virus-specific T helper cell clones can be restricted by MHC products different from serologically defined HLA-DR antigens. Tissue Antigens. 1983 Mar;21(3):238-45. Fleischer B. PMID: 6190261

The origin of HLA-DR"Br": exon 2 nucleotide sequence implicates possible gene conversion of DR1 by DR4-Dw10, DR5, or DRw6-Dw18. Hum Immunol. 1989 Nov;26(3):191-7. Bidwell JL, Bidwell EA, Sansom DM, Klouda PT, Bradley BA. PMID: 2575090

Analysis by molecular cloning of the human class II genes. Fed Proc. 1984 Dec;43(15):3025-30. Erlich H, Stetler D, Sheng-Dong R, Saiki R. PMID: 6094260

HLA-DRw6 as a risk factor for active cytomegalovirus but not for herpes simplex virus infection after renal allograft transplantation. Br Med J (Clin Res Ed). 1985 Sep 7;291(6496):619-22. Roenhorst HW, Tegzess AM, Beelen JM, Middeldorp JM, The TH. PMID: 2992676

Glycoprotein B from strain 17 of herpes simplex virus type I contains an invariant chain homologous sequence that binds to MHC class II molecules. Immunology. 2002 Sep;107(1):129-35. Sievers E, Neumann J, Raftery M, SchOnrich G, Eis-Hubinger AM, Koch N. Division of Immunobiology, Institute of Zoophysiology, University of Bonn, Germany. PMID: 12225371

Polymorphisms within the HLA-DRw6 haplotype. I. Restriction fragment length variation and its correlation with serology. The Journal of Immunology, Vol 134, Issue 5 3212-3217, Copyright © 1985 by American Association of Immunologists. ML Bosch, GM Schreuder, H Spits, A Termijtelen, MG Tilanus and MJ Giphart PMID: 2984285

HLA-DR2, -DR5, and DRw6 associated Dw subtypes correlate with HLA-DR beta and -DQ beta restriction fragment length polymorphisms. Proc Natl Acad Sci U S A. 1986 May;83(10):3361-5. Font MP, Gebuhrer L, Betuel H, Freidel C, Dausset J, Cohen D. PMID: 3010292

Biochemistry of HLA-DRw6: evidence for seven distinct haplotypes. J Immunol. 1986 May 15;136(10):3767-72. Haziot A, Lepage V, Freidel AC, Betuel H, Degos L, Charron DJ. PMID: 3486222

Hypoxia inhibits human bladder smooth muscle cell proliferation: A potential mechanism of bladder dysfunction. Neurourol Urodyn. 2004;23(4):342-8. Galvin DJ, Watson RW, O'Neill A, Coffey RN, Taylor C, Gillespie JI, Fitzpatrick JM. Department of Surgery, Mater Misericordiae University Hospital, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Ireland. PMID: 15227652


And of course, the ever-present fibromuscular dysplasia (FMD):

"Fibro-muscular dysplasia is known to be more frequently associated with ... the presence of HLA-DRW6 antigen."
hyper.ahajournals.org... (1989)
medind.nic.in/jac/t03/i2/jact03i2p139.pdf (2003)
www.indegene.com/Car/FeatArt/indCarFeatArt25.html (2003)

Etiologic factors in renovascular fibromuscular dysplasia. A case- control study. Hypertension, Vol 14, 472-479, Copyright © 1989 by American Heart Association CN Sang, PK Whelton, UM Hamper, M Connolly, S Kadir, RI White, R Sanders, KY Liang and W Bias Outpatient Clinical Research Center, Johns Hopkins Medical Institutions, Baltimore, MD 21205.
MeSH terms: HLA-DR6 Antigen
HLA-DRw6; HLA-DR6; Antigen, HLA-DR6; HLA DR6 Antigen
Human immune-response, D-related antigen encoded by the D locus on chromosome 6 and found on lymphoid cells.


.

[edit on 28-2-2005 by soficrow]



posted on Feb, 28 2005 @ 01:43 PM
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I don't see how this has ANYTHING to do with prions. Lots of proteins have hairpins in them and are not considered to be prions. The article makes no mention whatsoever of prions. Why the speculation?

Also, for this to be a prion like situation, you'd have to have both the infectious prion protein and an analogous host protein to nucleate prion formation. This is how prions replicate... nucleation of mis-folding in analogous proteins. To my knowledge HIV gag doesn't have a human analog.



posted on Feb, 28 2005 @ 01:45 PM
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Soficrow

I was unaware prions caused genetic changes. Do you... no I know you have relevant links, I would appreciate seeing a couple.

I thought prions infected by nucleation only. What genetic changes can be attributed to prion infections?

Thanks in advance.



posted on Feb, 28 2005 @ 02:17 PM
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More evidence of prions in HIV

But this can't be considered a prion, its a normal functional protein that doesn't replicate itself.



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