Lecture 27 Flashcards
Soft tissue
Closely packed cells with little ECM between
Connective tissue
Less cells more ECM
Components of ECM
Proteinaceous fibres embedded in a gel-like ground substance
Mechanical properties of ECM depend on
Amount of proteinaceous fibers
Type of proteinaceous fibers
Orientation of these fibers
ECM undergoes constant remodeling by
MMP = matrix metalloproteinases
Need zinc and include collagenases
Dysregulation of MMP
Spread of cancer cells
Types of fibrous proteins
Collagen
Elastin
Keratin
Tropomyosin
Characteristics of fibrous proteins
Low H2O solubility
Large amounts of repetitive secondary structures
Long cylindrical shape
Structural and strength
Collagens
Superfamily of proteins
Insuluble
In all tissue and organs but vary amount, more in cartilage, cornea, skin
Major ECM protein
Structure of collagen
Triple-helix structure
3 long individual alpha-chains > 600-3000 aa
25 different alpha-chains: same length but vary in primary sequence, encoded by diff genes
Homometric or heterometric
Diff mechanical properties
Center of alpha chains: repetitive aaa sequence rich in proline and lysine, glycine repeats each 3 aa
Hydroxylated proline and lysine by
Prolyl hydroxylase co factor with ascorbate, happen post-tl before triple helix formation
Add OH to form more H bonds, increase stability
Lysine: glycosylation by galactose or glucose
Collagen biosynthesis
Pre pro-alpha-chain with ER signal sequence > into ER, remove signal seq > hydroxylate proline and lysine > add sugar to selected hydroxylysine, pro-alpha chain
> 3 pro-alpha-chains form intra- & interchain disulfide bonds, with non-helical c/N terminal extensions = propeptides, pro-collage
> vesicles containing pro-collage bud off from ER > fuse with Golgi > secretory vesicles > release to ECM
>remove propeptides by C/N-pro-collagen peptidase > tropocollagen
Fragile & soluble to stable and insoluble, persistant
Fibillogenesis
Collagen molecules align in a staggered fashion overlapping its neighbors > cross linking due to lysyl oxidase > fibrills
Lysine by lysyl oxidase > allysine > aldehyde gp of allysine spontaneously nucleophilic addition with amino gp of lysine, form covalent bond, increase stability and insolubility
Lysyl oxidase dependent on
Cu2+
Copper chelating drug: penicillin
Inhibit this enzyme, reduce cross-linking: occipital horn syndrome and Menkes disease
Hole region
40 nm gap between adjacent collagen molecules in a row along the fibril axis
Sugar attached to 5’-hydroxylsyl residue in the hole region may be involved in the organization of fibril assembly
collagen involved in
Bone formation, site of bone mineralization
Collagen in teeth and bone is impregnated with calcium phosphate
Causes for Collagen disorder = collagenopathy
Genetic defects in collagen genes
Genetic defects in genes encoding enzymes involved in collagen biosynthesis
Dietary deficiency of vitamin C, required for enzyme
Deficiency in copper
Scurvy
Vitamin C deficiency
Inhibit hydroxylation of lysine and proline
Reduced interchain H bond, unstable collagen, unwound at low T
Subcutaneous extravasation of blood due to capillary fragility
Children: bone disease, hemorrhages, healing defects
Adults: hemorrhages, healing defects
Causes: malnutrition, chronic alcoholics, unsupplmented formula milk
Ehlers-Danlos syndrome = EDS
Inherited disorder
Defects in processing enzymes
Affects connective tissues: skin, joint, blood vessel
6 forms of syndrome
Flexible joints
Stretchy or fragile skin
Classical EDS
Type I and II
Mutations in the genes COL5A1 and COL5A2 encoding type V collage
Characterized by: Fragile hypertensible skin Joint hypermobility Delayed wound healing Hypotonia with delayed motor development
Mutated chains not secreted > degraded or accumulate > vascular problems
Osteogenesis imperfecta
Brittle bone disease, bone easily bend and fracture
8 forms, type I to VIII
COL1A1 and COL1A2 mutations
OI Type 1 = OI tarda
Often misdiagnosed as child abuse
Mutations in COL1A1 gene
Quantitative alterations: less synthesis of type 1 collagen, alpha1 and alpha2 chains
Characteristics: Bone fractures Blue or grey tint to the sclera Hearing loss in adulthood Retarded wound healing Rotation/twisting of the spine
OI Type II = congenita
Mutation in either COL1A1 or COL1A 2, most severe form
Point mutation and exon rearrangements in region coding for triple helical
Gly replaced by aa with bulky side chains
Prevent triple helix formation
Affected infants die in utero or shortly after birth from pulmonary hypoplasia
Deletion mutation of 84aa from alpha1 Col1A1 gene > shortened chains, prevent triple helix > all alpha chains degraded > lower levels of typr I collagen, lethal
2 structural elements for elastin fibers
Central core of elastin
Surrounding network of fibrillin microfibrils sheath
Elastin produced by
Fibroblasts and smooth muscle cells
Elastin structure
Single polypeptide 750 aa, long, fibrous, water-insoluble
Enriched in nonpolar aa: gly, ala, val
Proline and lysine, not glycosylatednor hydroxylated
Strech and flexibility: lungs, skin, uterus, bv
Dominant ECM in arteries
Production of elatin
Precursor named tropoelastin, secreted into ECM
Lysyl oxidase converts lys to allysine
Desmosine crosslinks: aldol condensation btwn 3 allysine and 1 lysine, yellow hue
Rubbery network
Microfibril sheath
Embed elastin
Composed of fibrillin, glycoprotein, scaffold
2 isoforms, fibrillin-1 and -2 encoded by FBN-1 and FBN-2
Marfan’s Syndrome
Defects in fibrillin 1 gene
AD
Results in:
Changes in mechanical properties of ECM
Loss of control of the bioavailability of many substances : TGF-beta
Excessive TGF-beta signaling > long bones, regulate connective tissue growth and architecture
Symptoms of Marfan’s Syndrome
Skeletal abnormalities: overgrowth of longbones, scoliosis
Ocular changes: bilateral subluxation or dislocation
Cardiovascular lesions: mitral valve prolapse, dilation of ascending aorta
Aortic hemorrhage
