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Supplement to CADASIL (for Biologists)

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发表于 5-14-2019 16:46:49 | 只看该作者 回帖奖励 |倒序浏览 |阅读模式
You may not be interested in this posting, which is for biologists.

Last night I had Note (d)(ii) Notch proteins
https://en.wikipedia.org/wiki/Notch_proteins
(A) If you can, manage to read the entire page.
(B) The introduction early on mentions DSL family ligands." Not until section 4 Ligand interactions does the page explain "the Delta/Serrate/Lag-2 (DSL) family of proteins which is named after the three canonical Notch ligands. Delta and Serrate are found in Drosophila while Lag-2 is found in C elegans [a kind of round worm, 1 mm in length]. Human contain 3 Delta homologs, Delta-like 1, 3, and 4, as well as two Serrate homolgs, Jagged 1 and 2."

I wrote, " 'The jagged 1 protein encoded by JAG1 is the human homolog of the Drosophila jagged protein.'   :from the Web."  This is wrong: Drosophila does not have "jagged." (What it does have is Delta and Serrate.)

* Lindsell CE et al, Jagged: A Mammalian Ligand That Activates Notch1. Cell, 80: 909, 910 (1995)
http://www.cell.com/cell/pdf/0092-8674(95)90294-5.pdf
("This clone was named Jagged [now Jag1; humans and rats have two similar genes: Jag1 and Jag2]  as it is most similar to, yet distinct from, Drosophila Serrate")

To sum up, Drosophila has Delta and Serrate ligands, whereas humans have Jagged 1 and 2 ligands.
(C) Heed section 3 Structure -- and its cartoon, which describes Drosophila, not humans.
* The Delta ligand is depicted as (from top) a DSL (Delta/Serrate/Lag-2) domain (in neon yellow), followed by EGF domains.
* Notch receptor is made up of (from top) a series of EGF-like domain
https://en.wikipedia.org/wiki/EGF-like_domain
(here a beta sheet has two strands (blue arrows) on the same plane)
, then three LNR (Lin-12/Notch) repeats (in green color, whose 3-D structure is shown at the top of the Web page), and (inside the cell) six ankyrin repeats (red) plus a PEST sequence (a square of deep red).
https://en.wikipedia.org/wiki/PEST_sequence
* Inside the nucleus, the blue oblong is "Suppressor of hairless" protein, sitting on DNA called E(spl) -- for "enhancer of split" where split is another name for Notch receptor, and enhancer of split are a cluster of genes regulated this way. When Hairless protein (green oval) binds to Suppressor of Hairless, the transcription of E(spl) is repressed. However, upon binding with ligand Delta, the Notch receptor breaks at the portion that crosses the cell membrane, releasing the intracellular portion to enter the nucleus, displace Hairless and binds to Suppressor of Hairless, activating transcription of E(spl) genes.

^ In C elegans, the same gene accounts for partial loss-of-function mutations in lag-1 and lag-2 and null mutations in glp-1. The glp stands for (abnormal Germ Line Proliferation), and lin (abnormal cell LINeage).
^ About nomenclature: why are they called alpha-helix and beta-sheet in protein's 3-D structure?  
(A) Yu J et al, Human Hair Keratin. Journal of Dermatological Science, 101: 56S (1993)
https://www.jidonline.org/article/0022-202X(93)90501-8/pdf
("The term 'keratin' is derived from a [Ancient] Greek word [noun neuter kéras] meaning 'horn' * * * Some of the first information regarding hair keratins came from the pioneering X-ray diffraction studies of [Englishman William] Astbury and coworkers. They found a characteristic alpha-pattern typical of hard keratin - containing tissues" such as hair, nail, mammalian claw and horn, but not bird claw)

Other keratins have "beta pattern."
(B) Alpha-keratin is found in all vertebrates (which includes birds and reptiles), and yet "β-keratins are found exclusively in reptiles and birds." Greenwold MJ et al, Dynamic Evolution of the Alpha (α) and Beta (β) Keratins Has Accompanied Integument Diversification and the Adaptation of Birds into Novel Lifestyles. BMC Evolutionary Biology, 14: 249 (2014).
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4264316/
(C) Eisenberg D, The Discovery of the α-Helix and β-Sheet, the Principal Structural Features of Proteins. Proceedings of National Academy of Sciences, 100: 11207 (2003).
https://www.pnas.org/content/100/20/11207

To sum up, α-keratin
https://en.wikipedia.org/wiki/Alpha-keratin
(view cartoon only)
is composed of α-helix in coiled coil, and β-keratin (which builds bird feather, beak and claw), of β-sheet.
https://en.wikipedia.org/wiki/Beta_sheet
^
(A) Bennett V and Stenbuck PJ, Identification and Partial Purification of Ankyrin, the High Affinity Membrane Attachment Site for Human Erythrocyte Spectrin. Journal of Biological Chemistry, 254: 2533, 2533 (1979)
www.jbc.org/content/254/7/2533.full.pdf
("We have named this protein 'ankyrin' from the Greek ankyra, which means anchor")

The Ancient Greek ἄγκυρα is transliterated as ankyra, though many online English dictionaries spell ankura (the English noun anchor ultimately is traced to ἄγκυρα).
(B) ankyrin repeat
https://en.wikipedia.org/wiki/Ankyrin_repeat
(consisting of two alpha helices separated by loops [in a module]; its namesake ankyrin contains 24" repeats)
(C) ankyrin
https://en.wikipedia.org/wiki/Ankyrin
("AnkyrinR [the protein encoded by human gene ANK1] enables erythrocytes to resist shear forces experienced in the circulation. Individuals with reduced or defective ankyrinR have a form of hemolytic anemia termed hereditary spherocytosis")
is a protein.
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