basic properties fibrillar proteins

insoluble

repeating secondary structure

hi molec wt

usually structural role

most abundant protein in body

COLLAGEN

Major organs/tissues affected by collagen defect

cardiovascular organs (aortic/arterial aneurisms, heart valve malfunction)

bone (fragility, fractures)

skin (poor healing, extra-stretchy)

joints (hypermobility, arthritis)

eyes (dislocation of lens)

Type I collagen amino acid composition

33% Gly, 10-14% Pro, 10% Hydroxyproline, 1% Hydrolysine

Gly every 3rd residue and Pro or Hyp every 3rd in same region:

-Gly-Pro-Yand Gly-X-Hyp

enzymes catalyzing posttranslational modification of Pro and Lys to Hyp and Hydroxylysine

and cofactors

lysyl hydroxylase

prolyl-4-hydroxylase

prolyl-3-hydroxylase

cofactors: Fe²⁺, oxygen, alpha-ketoglutarate, ascorbic acid

Scurvy

Ascorbic acid (vitamin C) deficiency--lysyl/prolyl hydroxylase cofactor

poor collagen synthesis-->supporating wounds, abnormal bone growth in children (formula-fed babies succeptible), loss of teeth, malaise

1st noted by Hippocrates

connection to vit C noted by Charles Glen King

Structural consequences of amino acid composition of type I collagen

Gly--small, fits into core of structure

Pro--helix-breaker, regular alpha helix doesn't form

Hydroxyl group--H-bonds with other chains (crosslinking)

Consequence of collagen glycosylation

available for interaction w envt

1 collagen strand

polyproline type II helix

loose, left-handed, 3 residues/turn

each chain labeled an alpha chain

3 alpha chains

forms 3-member superhelix (Gly in every 3rd pos)

right-handed triple helix

carbonyl group conformation of collagen superhelix

carbonyl groups point toward neighboring chains-->interchain H-bonds--> stability at body temp (based on Hyp concentration: high conc=more stable)

collagen fibrils

triple helices aggregate in quarter-staggered arrays, crosslink

collagen fibers

aggregation of fibrils-->structural strength or filtering meshwork

collagen's inter-fiber crosslinks are ______ bonds between __(amino acid)__ and ___(a.a.)____

covalent, lysine and allysine

telopeptides

N and C terminal segments of triple helical region (crosslinking sites)

enzyme that converts lysine to allysine

lysyl amino oxidase

COPPER-DEPENDENT

Collagen synthesis inside the cell

RER ribosomes: translation of 3 alpha-chains "preprocollagen"

RER lumen: SIGNAL PEPTIDASE cleaves signal peptides from ends "procollagen"

Hydroxylation of Lys/Pro (LYSYL/PROLYL(3/4)HYDROXYLASE)

Glycosylation fo Hydroxylysine (and Arg)=stabilization

disulfide bond formation (intra/interchain)

triple helical structure

Golgi: glycosylation completed/exocytosed

Collagen synthesis outside of cell

propeptides cleaved from ends of procollagen (PROCOLLAGEN PEPTIDASE)--> "tropocollagen"

tropocollagens form fibrils which form fibers

maturation: crosslinks form and stabilize "collagen fiber"

mineralization

after collagen synthesis, mineralization may occur to further strengthen structure

Collagen degradation enzymes

collagenase: clips triple helix (hydrolysis)

gelatinase (MMP): unwinds helix

Major categories of collagen (3)

fibrillar: types I-III, V, XI

network-forming: IV

fibril-associated: IX & XII

Type I collagen chains

2 alpha-1, 1 alpha-2

Osteogenesis Imperfecta

mutations in alpha-I or -II in type I collagen

unstable procollagen helices which are degraded and cannot enter ER

Ehlers-Danlos syndrome (4 main types)

IV

VI

VII

IX

 4 6 7 9

Ehlers-Danlos IX (9)

 X-linked recessive deficiency in lysyl oxidase results in decreased crosslinking OR copper deficiency (hyperextensible skin, bladder diverticulae, skel deform.)

Ehlers-Danlos VII (7)

autosomal dominant mut-->inability to remove end term propeptide (hypermobility, dislocations, soft skin)

Ehlers-Danlos IV (4)

autosomal dominant mut --> type III collagen (thin skin/hollow organs, ruptured arteries)

Ehlers-Danlos VI (6)

autosomal recessive def in lysyl hydroxylase (velvety skin, scoliosis, hypermobility, ocular injuries)

Elastin, basic structure

lacks regular secondary structure, lots of allysine (converted from Lys again by LYSYL OXIDASE--copper-dependent)

crosslinking: desmosine and isodesmosine

Elastin degradation enzyme and inhibitor

elastase: serum protease cleaves after apolar amino acid

inhibited by: alpha-1-antitrypsin

Emphysema

deficiency or damage by smoking of alpha-1-antitrypsin, which inhibits elastase

result: elastase chops up lung tissue

desmosine and isodesmosine in elastin

covalent crosslinking responsible for elastic quality

Microfilament, protein components

actin (polymerized globular subunits [G-actin]), modulates cell shape and drives locomotion

myosin, motor protein whose heads bind to actin and using APT-->cell mvt

microtubule structure

globular alpha- and beta-tubulin form dimers, which arrange into hollow tubes

microtubules organize into centrioles, cell mvt, shape and organization

+ end (fast-growing end) oriented toward cell periphery

Colchicine

meadow saffron plant product--disassembles microtubules of WBC, inhibiting inflammation caused by uric acid precipitation (gout)

Taxol

Pacific yew tree extract--anti-cancer drug, binds beta-tubulin subunits in microtubules, preventing cell division

Kinesins and dyneins

microtubule motor proteins

kinesin: mvt towards plus end "anterograde vesicular traffic", 2 heads bind microtubule (ex: move neurotransmitters in axons)

dynein: mvt toward minus end "retrograde vesicular traffic"

Keratin

intermediate filament protein

exclusively structural

soft: internal body structures

hard: skin, hair, claws

structure: coiled coils (alpha-helix dimers), 7 residue repeating units (1st and 4th apolar)

dimers assemble in multimers stabilized by disulfide bridges

Hair styling

reduced (break disulfide bonds), then oxidized (perm/straightening)

curls caused by crosslinking between cysteine residues

Epidermolysis bullosa simplex (EBS)

weak skin keratin, blistering

alpha-1-antitrypsin

inhibits elastase (which degrades elastin)