Lecture 7 Fibrous Proteins and Connective Tissues

Fibrous proteins

long protein strands or sheets
-are adapted for a structural function
-Give strength and/or flexibility to protein structures
-Are simple repeating elements of secondary structure
-Are H2O insoluble due to high concentrations of hydrophobic residues

Globular proteins

Proteins folded into a spherical or globular shape

Membrane proteins

embedded in hydrophobic lipid membranes

Intrinsically disordered proteins

lack stable tertiary structures

α-keratin helix

is a right-handed α helix
-Two stranded of α-keratin, oriented in parallel, wrap about each other to form a super twisted coil of coils
-Super twisted helical path is left-handed

hair contains

many α-Keratin filaments
-Rich in hydrophobic residues: Ala, Val, Leu, Ile, Met, and Phe
-Cross-links stabilized by disulfide bonds

Collagen

a fibrous protein found in connective tissue
-Secondary structure = left=handed, repeating tripeptide
-Tertiary and quaternary structure = right-handed twist of 3 separate polypeptides

Covalent cross-links

increases collagen strength
-Collagen is cross-linked by covalent (strong) bonds involving Lys, HyLys (5-hydroxylysine), or His

Collagen punctal plugs

treatment for dry eye disease
-prevents tears from draining and thus keep your tears on your eye longer

Collagen I

skin, tendon, vascular ligature, organs, bone

Collagen II

Cartilage

Collagen III

Reticular fibers, commonly found alongside type I

Collagen IV

Basal, lamina, the epithelium-secreted layer of the basement membrane

Collagen V

Cell surfaces, hair and placenta

Osteogenesis imperfecta

AD mutation in type 1 collagen. Weak bones and irregular connective tissue, mild to lethal

Chondrodysplasias

suspected type 2 collagen mutation. Skeletal disorder

Ehlers-Danlos Syndrome

Collagen type 3 mutation. Deformities in connective tissue

Alport syndrome

X-linked, AR, or AD. kidneys and eyes, loss of hearing

Osteoporosis

Not genetic. Reduced levels of collagen in the skin and bones

Knobloch syndrome

collagen XVIII gene mutation, protrusion of the brain tissue and degeneration of the retina

sclera

is made of collagen fibers which randomly interweave
-Random pattern leads to opaque white color and scleral strength

Scurvy

caused by a lack of vitamin C
-characterized by general degeneration of connective tissue
Vitamin C is required for the hydroxylation of proline and lysine in collagen

Fibroin

-The main protein in silk
-Predominantly β conformations
-Rich in Ala and Gly = no bulky side chains, very compact
-Stabilized by hydrogen bonding and van der Waals interactions

Connective tissue

-Made up of cells, fibers, and a gel-like "ground" substance
-Provides support, protection, and structure to other tissues and organs
-Stores fat, transports nutrients, and helps repair damaged tissue
Examples: Bone, cartilage, fat, blood, and lymphatic tissue

Connective tissue proper

-Loose (areolar) -surrounds trachea, blood vessels, and digestive tract. Contains lots of fibroblasts
-Dense (irregular) - dermis. Predominantly collagen in random formations

Specialized connective tissue

-Dense (regular) connective tissue - Tendons. Predominantly collagen in ordered patterns
-Cartilage
-Bone
-Adipose tissue
-Blood
-Hematopoietic tissue

Hereditary CT disease

-Marfan Syndrome

-Ehlers-Danlos syndrome

-Osteogenesis imperfecta

-Stickler Syndrome

-Epidermolysis bullosa

-Arterial tortuosity syndrome

-Loeys-Dietz syndrome

Acquired CT diseases

-Systemic lupus erythematosus (SLE)

-Systemic sclerosis (SSc)

-Sjogren Syndrome (SS)

-Mixed connective tissue disease (MCTD)

Polymyositis

-Dermatomyositis

-Polymyalgia Rheumatica

-Seronegative connective tissue diseases

-Ankylosing spondylitis

-Psoriatic arthritis

-Reactive arthritis

-Enteropathic arthropathy

Marfan syndrome

-Mutations of fibrillin-1 (FBN1)
-Long arms/legs, hands/feet, fingers/toes
-Hyperextendable joints
-Enlarged aorta
-Subluxation

Sjogren's Syndrome

Chronic inflammatory autoimmune disease
-Primarily affects tear and saliva glands, but other glands are affected
-Aqueous deficient dry eye

Ankylosing Spondylitis

Chronic inflammatory autoimmune disease
-Causes of fusion of spine and sacro-iliac joints over time
-Often associated with Uveitis
-HLA-B27 ("CRAP")

Ankylosis

stiffening of bones due to fusion

Spondylitis

inflammation of the spine

Amyloid fiber

a protein is secreted in a misfolded state and converted to an insoluble extracellular fiber

Amyloid disease

Type 2 diabetes, Alzheimer's disease, Huntington's disease, and Parkinson's disease

formation of disease-causing amyloid fibrils

-Native amyloid has a β-sheet
-Misfolded β amyloid promotes aggregation and formation of an amyloid fibril
-Phenylalanine

Alzheimer disease

associated with extracellular amyloid deposition by neurons, involving the amyloid-β peptide

Parkinson disease

misfolded form α-synuclein aggregates into spherical filamentous masses called Lewy bodies

Huntington disease

involves the intracellular aggregation of huntingtin, a protein with long polyglutamine repeat

Cystic fibrosis (CF)

caused by defect in the membrane-bound protein cystic fibrosis transmembrane conductance regulator (CFTR)
-Deletion of a Phe residue causes improper protein folding

Prion protein (PrP)

misfolded brain protein
Prions turn native proteins into misfolded prion proteins

Transmissible spongiform encephalopathies (TSEs)

=Prion Diseases
Transmissible fatal neurodegenerative diseases in humans and animals

BSE (bovine spongiform encephalopathy)

- mad cow disease
- causes the cows to lose motor coordination and affects behavior

CJD (Creutzfeldt-Jakob disease)

Memory decline behavioral changes, lack of coordination, visual disturbances

Ehler's Danlos syndrome

-Elastic skin that bruises easily
-Hyperflexible joints
-Mutations in COL5A1 and COL5A2 -> fibrillar protein assembly