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Biochemistry 203: Structural Proteins

The previous unit was about transport proteins, which are usually globular and contain alpha helices and beta sheets. Structural proteins are the most abundanct kind of proteins, and they are water insoluble and contain proportionally more beta sheets. There are three major groups, and a few other kinds, of structural proteins.

1. microfilaments (70 angstroms across)
2. intermediate filaments (100 A)
3. microtubules (240 A)
4. extracellular fibers (spider silk, collagen, keratin)
5. motor proteins (cytoskeleton that uses ATP to do work)

MICROFILAMENTS serve two purposes: 1. movement and 2. structure. Enzymes (specifically proteases) are needed to cut the chain.

G-actin is globular, made up of 375 aa's. It has a cleft for ATP binding, hydrolyzing it to ADP (biphosphate) and Pi (inorganic phosphate).

F-actin is a polymer of actin residues, making a long chain or "fibron". The chain is helical. "Older" G-actin residues hang onto the ADP that is leftover from when they were bound to the chain. "Newer" G-actin residues bind ATP to form links to more residues. Either end of the chain can have a CAP which prevents gain or loss of residues. These proteins provide motility by way of their growth, called "treadmilling" (when the chain gains on one end and looses on the other) or "cell crawling". WBC's migrate toward infection (which gives off cytokines) via diapedisis, this is called chemotaxis. Cancer cells metastasize this way too.

diapedisis

MOTOR PROTEINS

MYOSIN = a motor protein associated with actin (in muscles). Has a head (looks like two leaflets), neck and tail (2 tails twining) region. The head and neck are the "active" region, containing binding pockets for actin and ATP. Myosin neck flexes 70 degrees, binds and releases actin in a "racheting cycle". There is a corresponding conformational change in the myosin head. Myosin moves up the actin chain 7.5nm per flex. Defects in myosin coding from the genes can cause hearing deficits due to bad stereocilia in the inner ear.

myosin: thick, has binding sides, 3.5nm between ATP and actin binding sites

actin: thin, fibrous, 5.5nm between subunits

TUBULIN forms microtubules, is a globular protein with alpha and beta subunits. Tubes resist bending more than rods, giving structural integrity. Examples in nature: bamboo, bones. Cilia and flagella are made of microtubules, as well as the spindle apparatus that is present in mitosis (cell division). Microtubules are rapidly assembled and disassembled. Each tubulin monomer is 450 residues. Protofilaments are made of alpha and beta dimers, and the alpha end of the dimer links to the beta on the chain leaving a terminal beta. These subunits build a curved sheet which zips closed to form a tube that is 13 crosslinked protofilaments around. End are called (+) or (-) and the (+) end grows twice as fast as the (-) end. Disassembly looks like a frayed rope--the protofilaments separate first, and then are broken down. The subunits have a binding site for GTP which fuels making new bonds, but then is buried during chain formation.

COLCHICINE blocks microtubule growth, and has been used in mitosis microscopy studies because it stops mitosis wherever it is. Also causes depolymerization. Was considered as a cancer drug but is too nonspecific. The mechanism: binds between alpha and beta subunits and weakens lateral contact so the tube can't connect.

TAXOL from the yew tree was recently synthesized, and is similar to colchicine bey stopping microtubule assembly. It is different in that it does not cause depolymerization, instead it stabilizes the tubule by binding the beta subunits in the assembled microtubule (not free betas). This is a better cancer treatment but still is nonspecific.

KINESIN is a microtubule motor protein similar-looking to myosin, with the double head and twined tails. The head is 10nm across and consists of an 8stranded beta cheet with 3 alpha helices. It is different because at the end of the tails it has light chains which bind to cargo, and because the heads walk. The cargo is usually a vesicle, and kinesin's light chains bind to membrain proteins of the vesicle. Kinesin walks hand over hand along a strand of actin to transport the goods without loosing any. It can also move in an inchworm fashion. It uses lots of ATP, 100 per cycle (2 steps). Each step is 80 A in length, and so the cargo moves 160 A per cycle.

INTERMEDIATE FILAMENTS are 16-32 peptide chains in cross section. When these chains split up we get split ends!

KERATIN is an INTERMEDIATE FILAMENT protein that forms a coiled coil. Alpha keratin is present in hair, nails and skin. Increased disulfide crosslinking gives it hardness. It is alpha helical, and every 4th residue is hydrophobic, helping it to make the tight coil by having a "hydrophobic strip" down the middle. There are 3.6 residues/turn.

Beta Keratin is silk, aka fibroin. It is found in feathers and scales. Silkworm fibroin is made of antiparallel beta sheets with high tensile strength. It contains lots of valine and tyrosine, and tends to be compact/folded, giving it stretchiness.

monomer < dimer < tetramer < octamer < intermediate filament

COLLAGEN is the most abundant vertebrate protein of all. It holds us together. It is a major component of the bone matrix, tendons and skin. The fundamental unit of it is tropocollegen, which is a triple helix. Three left-handed polymers, twisted together in a right-hand direction. Each 3rd residue is a glycine, which is small to fit in the middle of the chain. GLY-X-Y-GLY-X-Y etc. The Y's are often hydroproline which helps stabilize the twist with hydrogen bonds between adjancent strands. Vitamin C is needed to make hydroproline from regular proline.

Scurvy is a disease caused by a lack of vitamin C. Lesions in the skin are caused by a collagen being unable to crosslink. The Brits became known as limeys because they learned that eating lime prevents scurvy.

Gin & tonic as medicine: quinine = antimalarial, lime for scurvy, and gin for the relaxation of booze.

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