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Transcript
CLINICAL ASPECTS OF BIOCHEMISTRY PROTEINS AND DISEASE MIKE WALLIS Structural/fibrous proteins Lectures 2-3: Elastin, Resilin, Silk, Keratin ELASTIN • Connective tissue - especially ligaments, blood vessels, trachea and bronchi. Very stretchy. • Elastic fibres - not striated - fibrous and amorphous component (amorphous component is elastin). • Very insoluble; more soluble form extractable from Cu2+ deficient animals - more Lys, less cross links. This is tropoelastin/proelastin. • 700-800 aas in peptide chains.. Rich in non-polar aas (esp. Gly, Ala, Val, Pro); no His, Cys, Met, Trp. • Little recognisable secondary structure, though maybe 15-20% ahelix. • ~33% Gly, ~20% Pro and some HydroxyPro and HydroxyLys. Sequences from tropoelastin -Pro-Gly-Val-Gly-Val-Pro-Gly-Val-Gly-ValPro-Gly-Val-Gly-Val-Pro-Gly-Val-Ser-ValPro-Gly-Val-Gly-Val-Pro-Gly-Val-Gly-Val- and repeats of: -Lys-Ala-Ala-Lys-Lys-Ala-Ala-Ala-Lys- Tropoelastin Elastin crosslinks - desmosine Elastin cross link formation Cu2+ Lysyl oxidase Oiled-coil model for elastin "oiled coil" desmosine cross links ELASTIN DEFECTS Williams syndrome - growth defects, cardiovascular problems, mental retardation.. Supravulvular aortic stenosis - cardiovascular problems Due to deletion of all or part of elastin gene, or (less commonly) substitutional point mutations in elastin gene Elastin defects may also be associated with vascular problems, ageing etc. THE ELASTIN GENE Cross link domains Elastomeric domains VARIOUS ELASTOMERIC PROTEINS (see Tatham & Shewry, 2000) RESILIN Very elastic protein of insect cuticle (Weis-Fogh, 1960) Very insoluble >33% Gly, 9-16% Pro, No Met, Cys, HydroxyPro Resilin - putative crosslinks (Anderson) Presumably derived from Tyr SILK FIBROIN •Main protein of silk (75%); the other major protein is sericin •Very strong fibre; resistant to tension (non-stretchy) but flexible •Very simple aa composition: ~46% Gly, 29% Ala, 12% Ser (c.f. sericin: 37% Ser, 17% Gly, 16% Asp) •b-pleated sheet; close to fully extended (~6.9Å repeat distance) •Sheets pack on top of each other; no covalent crosslinks; Hbonds, V de W's forces and hydrophobic interactions stabilise Repeating unit in silk fibroin Fibroin polypeptide chain: Mr ~ 370,000; ~65% 'crystalline', ~33% amorphous; crystalline has ~50 repeats of 59 aa unit: -Gly-Ala-Gly-Ala-Gly-Ser-Gly-Ala-Ala-Gly-[Ser-Gly-Ala-Gly-Ala-Gly]8-Tyr- b-PLEATED SHEET b-PLEATED SHEET SILK FIBROIN KERATIN REVISION You have come across keratin in several previous lecture courses, including Cellular Biochemistry (lectures by Wallis and Bacon) and ETS (lectures by Woolfson) and so should already know the answers to most of the following questions, Use them to revise and if necessary expand the topic. I shall run through them quickly in the lecture if time permits. 1.How many keratin genes and types are there in humans? 2.Where do keratins occur? What is their relation to the cytoskeleton. 3.What is the main secondary structure found in keratin? 4.Keratin super secondary structure comprises coiled coils. What does this mean? What is the significance of "heptad repeats" for this? KERATIN - REVISION (cont.) 5. How long are individual keratin molecules? How are they incorporated as subunits into keratin superstructures? What is the significance of "acidic" and "basic" keratins in this respect? 6. What are the main crosslinks in keratin? How can they be broken to partially solubilise the protein? How does increased crosslinking affect keratin's properties? 7. Keratin is the main component of hair. How are individual keratin molecules organised in a hair fibre? 8. Changes in keratin structure underlie temporary and permanent waving of hair. How? 9. If your hair grows at one cm per month, how many turns of alpha helix per second does this represent? 10.Epidermolysis Bullosa Simplex is an inherited human disease. What are its symptoms? What is its molecular basis? Is it dominant or recessive? How frequent is it? The a-helix Keratin Superstructure Wool fibre (200,000 Å) Packed dead cells (20,000 Å) Macrofibril (2,000 Å) Microfibril (80 Å) Protofilaments (20 Å) Alpha helix (5 Å) ORGANIZATION OF KERATIN FIBRILS