Examination of the protein sequence of insulin-like growth factors reveals strong heparin-binding domains (triplet of basic amino acids) that are also associated with internalization. Similar heparin internalization domains are also found on allergens and autoantigens. It was a small leap to expect that IGFs would also become autoantigens under inflammatory conditions that minimize heparan sulfate proteoglycan production.
Triplets of Basic Amino Acids Internalize Proteins
In several articles on this blog, I have discussed proteins that are internalized by their heparin binding domains. Heparin binding domains consistent only of a pair of basic amino acids, e.g. RK, flanked by one or more basic amino acids within a hydrophobic sequence of protein, are not sufficient to mediate internalization on heparan sulfate proteoglycans. A triplet of basic amino acids is usually required. Simple inspection of amino acid sequences is sufficient to identify these regions.
Internalization Triplet Identified in Insulin-like Growth Factor Binding Proteins
I noticed in a paper that insulin-like growth factors bind to epidermal growth factor receptors. I have previously written an article showing that EGF1 binds to its receptor via heparin, i.e. both the EGF and the receptor have heparin-binding domains. So I suspected that IGFs also had heparin binding domains. Inspection of the sequences readily identified simple heparin binding domains with pairs, but not triplets of basic amino acids. A search of the literature confirmed that heparin mediated IGF binding to receptors. A further search indicated that the heparin binding domains from proteins that bind and control the activity of IGFs could mediate internalization of proteins into cells and also into nuclei.Internalization Triplets Are Associated with Allergens and Autoantigens
I have previously noted that all allergens and autoantigens have internalization triplets of basic amino acids. The presence of these triplets in IGF binding proteins suggested that IGF binding proteins might also be autoantigens. A quick check of the literature showed that antibodies against IGFs themselves frequently occur in type I diabetes. This suggests that the IGF-binding protein complexes are internalized and IGFs are immunologically presented during inflammation to produce anti-IGF antibodies. It is interesting that the other autoantigens for type I diabetes, e.g. transglutaminase, also have the expected internalization triplets.
references:
Maruyama T, Murayama H, Nagata A, Shimada A, Kasuga A, Saruta T.
Anti-insulin-like growth factor-1 autoantibodies in type 1 diabetes. Ann N Y Acad Sci. 2002 Apr;958:267-70.
Miao D, Yu L, Eisenbarth GS. Role of autoantibodies in type 1 diabetes. Front Biosci. 2007 Jan 1;12:1889-98.
Goda N, Tenno T, Inomata K, Shirakawa M, Tanaka T, Hiroaki H. Intracellular protein delivery activity of peptides derived from insulin-like growth factor binding proteins 3 and 5. Exp Cell Res. 2008 Aug 1;314(13):2352-61. Epub 2008 May 29.
4 comments:
If you tried to explain heparin to a second grader, how would you do it? I am wanting to understand this more but no one else seems to cover it.
I also find it interesting that in many of the conditions you discuss heparin, I have also run across these same conditions while pub med digging, and they respond to the same dietary measures, have gluten issues and ASCA's. So I naturally want to get an understanding of heparin.
Mrs. Ed,
Heparan sulfate as pop beads for second graders:
The second graders (SGs, or glycosyl transferase enzymes that add sugars) carry around either of two colors of pop beads (pink and turquoise) until they find an adult (another protein) with an attached yellow bead. The SGs take turns adding to the growing chain of beads started by the yellow bead (-Y-P-T-P-T-P-T). Other SGs can add green beads (sulfates) to some of the pink and turquoise beads. [The adult with the long chain is a heparan sulfate proteoglycan, HSPG.]
HSPGs all get pushed out of the house, but get stuck in the yard. On the edge of this gated community (tissue/organ), the HSPGs accumulate and block all of the exits [This is the basement membrane made of HSPGs/proteins and the sealant for kidney, gut and brain blood vessels, e.g. the blood brain barrier.]
In some houses, there are people with tools that chop up the bead strings into bracelets (heparin) and those bracelets are dumped outside if emergency sirens are blasted in the neighborhood. [This is the release of heparin along with histamine in response to mast cell stimulation. This is also how heparin is produced in the gut and why pig intestines are the source of pharmaceutical heparin.] Sirens also stop the SGs from making more HSPGs. [Inflammation makes the BBB leaky, makes kidneys leak protein, etc.]
FedEx carriers talk to the HSPGs that are coming out the back door of the houses and going back in the front door. [HSPGs recycle every six hours, and the FedEx carriers are hormones or LDL.] The FedEx carriers hand off their packages while holding onto the pop bead chains.
Dogs outside also hold onto the pop bead chains. [The teeth of the dogs are basic amino acids, heparin binding domains.] Some of the dogs (e.g. allergens, autoantigens) get dragged inside the house along with HSPGs and some of the FedEx carriers, by mistake if the sirens are too loud. [This is the basis for allergies and autoimmunity.] Neighborhood monitors (Tregs) usually come around to make sure that there are no dogs or FedEx carriers in the wrong houses, unless there is a recession (Treg production stopped by defective gut flora).
Primary school is hard work.
Heparin mystified me, too, until now. Thanks to you Mrs Ed for asking and thanks to you Dr. Ayers for that delightful and thoroughly understandable explanation.
Pop beads, indeed. When I was a second grader back in about 1970, I had a neighbor who let me play with her pop beads. I thought they were so elegant.
I wonder who will now want pop beads explained...
Thank you!!! This was very helpful. Now when I read about heparin I can visualize what the pop-beads are doing. I have to do this to wrap my brain around stuff..if this were an ant-hill/restaurant/etc, it really helps. Now I can use pop-beads too.
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