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Glycoproteins vs. Proteoglycans
- both are Proteins conjugated to saccharides
- Glycoprotein: protein >> carbohydrate; no repeat unit of saccharides
- Proteoglycans: carb >> protein; polysaccharide w/ repeat units
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Proteoglycans are ________
glycosaminoglycans and mucopolysaccharides
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Vast majority of glycoproteins and proteoglycans function in _______
the extracellular matrix (ECM)
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Overview of glycoproteins:
- carbohydrate chain short
- no serial repeats
- often branched, not linear
- neutral or charged
- variable amounts of carbs
- wide range of functions
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Sample Glycoproteins
- Structural molecule: Collagens
- Lubricant: Mucins
- Transport molecule: Transferrin, Ceruloplasmin
- Immune: Immunoglobulins, Histocompatibility antigens, Blood group determinants (ABO)
- Hormone: HCG, TSH
- Enzymes: Alkaline phosphatase
- Blood clotting: Fibrinogen
- Cell surface recognition: Lectins
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There are two types of glycosidic links in glycoproteins:
O-glycosidic link and N-glycosidic link
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O-glycosidic link
- -OH + -OH -> -O- + H2O
- between galactose or glucose and the hydroxyl group of hydroxylysine (collagen), OR
- between N-acetyl galactosamine and serine or threonine (blood group substances and salivary mucins).
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N-glycosidic link
- -OH + -NH2 -> -NH- + H2O
- between N-acetylglucosamine and
- asparagine. There are two types:
- A. High mannose on the other side of the sugar
- B. Complex. eg in addition to mannose they may contain N-acetylglucosamine, galactose, frucose and N-acetylneuraminic acid (sialic acid)
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Glycoproteins are synthesized on _______, then transported via ______ to the ____ for sorting
- ribosomes attached to the RER
- vesicles
- Golgi
-
saccharide units come from
- UDP-glucuronic acid
- UDP-N-acetylgalactosamine
- GDPmannose
- CMP-NANA (for Sialic acid)
- All catalyzed by specific glycosyltransferases
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For synthesis of O-linked glycoproteins, addition is _____. For N-linked glycoproteins, the chain is _______ formed on ______ and then transferred to the protein.
- direct
- indirectly
- dolichol pyrophosphate
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Degradation of the saccharide chains of glycoprotein is achieved by _____ enzymes present in _______. The enzymes act on ____ of the chains on a _______ basis.
- hydrolytic
- lysosomes
- the ends
- last-on-first-off
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Defect of glycoprotein degradation: _____
cause
symptoms
- I-cell disease
- deficiency in lysosomal enzymes, which do not aquire the targeting signal, mannose 6-phosphate.
- Fibroblasts have dense inclusion bodies (I-cells)
- lysosomes engorged with indigestible substrates
- leading to death in infancy
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Proteoglycans are usually ______ components of the ________ (exception: ______); some have a ______ role, or ________ roles
- structural
- extracellular matrix
- heparin (normally intracellular)
- lubricant: bind large amounts of water
- cell/cell signalling and adhesion
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The proteoglycans include
- hyaluronic acid: GlcUA-β1,3-GlcNAc
- heparin: GlcUA-α1,4-GlcN
- chondroitin sulfate: GlcUA-β1,3-GalNAc
- dermatan sulfate: IdUA-β1,3-GalNAc
- heparan sulfate: GlcUA-α1,4-GlcN
- keratan sulfate: Gal-β1,4-GlcNAc
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Proteoglycan monomers are _______ bound to _________ in association w/ _________ in a _______ arrangement.
- non-covalently
- a hyaluronic acid molecule
- linker proteins
- "bottle brush"
- This is how the proteoglycan aggrecan forms.
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STRUCTURE OF PROTEOGLYCANS (GAGs)
Proteoglycans usually consist of _____ _____ linked to ______, which typically consists of __________ with _______.
- a core protein
- covalently
- a glycosaminoglycan
- a long polysaccharide chain
- a repeating disaccharide motif
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STRUCTURE OF PROTEOGLYCANS (GAGs)
Proteoglycans are poly_____, which comes from the ______ and/or ______ groups. The ______ group is on either _______ or _______.
- anionic
- carboxyl
- sulfate
- carboxyl
- D-glucuronic acid
- its epimer L-iduronic acid
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STRUCTURE OF PROTEOGLYCANS (GAGs)
The repeating disaccharide is ______ linked to a ____ residue on the protein through a __________ sequence.
- glycosidically
- serine
- galactose-galactose-xylose-serine
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Synthesis of proteoglycans
where
The units in the saccharide chains are elongated in _______, donated from ___ derivatives. Last step is _____ of some _____ sugars.
Defects:
defects
Golgi
- alternating acidic/amino sugars
- UDP
- sulfation
- amino
- Defects in sulfation -> chondrodystrophy
- genetic defects affect proper developement and maintenance of the skeletal system
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DEGRADATION OF PROTEOGLYCANS
Some proteoglycans must be _______ first
Degradation of the saccharide chains is achieved by ______ enzymes present in ______. The enzymes act on the ends of the chains on a ______ basis.
- phagocytosized
- hydrolytic
- lysosomes
- last-on-first-off
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MUCOPOLYSACCHARIDOSES (MPS)
- Rare inborn errors in the degradation of glycosaminoglycans
- mental retardation and/or structural defects
- Type I-IV, VI, and VII
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MPS Type I
- Hurler’s syndrome
- a deficiency of alpha-L-iduronidase
- Heparan sulfate and dermatan sulfate accumulate. growth and mental retardation with characteristic facial changes
- 1:100,000
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MPS Type II
- Hunters syndrome
- deficiency of iduronate sulfatase
- X-linked inheritance (male only)
- 1:100,000; only affects males
- delayed tooth eruption and possible mental retardation
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MPS Type III
- Sanfilipo’s syndrome
- deficiency of one of four degradative enzymes: three hydrolases and one N-acetyltransferase.
- severe mental retardation and mild structural features
- 1:70,000
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MPS Type IV
- Morquio Syndrome
- Deficiency of galactose-6-sulfatase or betagalactosidase
- accumulation of keratan sulfate
- normal intelligence but severe deformity
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Fibrous proteins — _______
solubility
stability
half-life
mechanical property
- collagens and elastin
- • Insoluble
- • Stable
- • Long biological half-life
- • High tensile strength and contractibility, respectively, resulting from their unique structures
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These proteins function in ________
the extracellular matrix (ECM)
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______ are the most abundant proteins in the human body, comprising ____% of all proteins. Almost __ have been identified! Genetics:
- Collagens
- 25-30
- 30 (different collagens)
- MANY genes throughout the genome
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Types of collagens
- Fibril forming (rope-like; hallmark collagen): I-III, ...
- Network forming (mesh-like): IV, VII, ...
- Fibril associated (linking fibrils): IX, XII, ...
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Collagen structure
- All triple-helically structured
- Each chain has the amino acid sequence Gly-X-Y
- X is usually proline
- Y is usually (hydroxy)-proline and (hydroxy)-lysine
- Gly has small side chain, tolerate the structure
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Synthesis of collagen
- prepro-a chain translated (RER)
- signal sequence cleaved, forming pro-a chain
- lys and pro residules are selectively hydroxylated
- some hydroxylys are modified w/ glucose and/or galactose
- three pro-a chains assemble: C-terminals form inter- and intra-chain disulfide bonds; tripple-helix forms
- triple-helix pro-a secreted to ECM from golgi vacuole
- extracellular enzyme procollagen peptidase cleaves off the terminals to form collagen
- collagen self assemble (in a regularly staggered way) and later on cross link to form the fibrils
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Staggered packing of collagen
- w/ negative staining, a banding pattern is generated
- where there is a gap becomes darker; places w/o gap are lighter
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Hydroxylation of proline and lysine
enzyme
co-factor
- prolyl hydroxylase and lysyl hydroxylase
- Fe2+ and ascorbic acid
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Cross-linking between the collagens require
enzyme _______ and co-factor ______
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Deficiency of Cu2+ causes ________, and ______ results from too much Cu2+ accumulated in the body.
- Menkes disease
- Wilson's disease
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Scurvy
- A non-genetically based collagen disorder
- Directly results from ascorbic acid deficiency.
- Frequently presents as easily bruised skin,bleeding gums, loosened teeth, “corkscrew hairs”,poor wound healing.
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Genetically-based collagen disorders:
- Osteogenesis imperfecta (OI; “brittle bone disease” since bones easily fracture; four types)
- Ehlers-Danlos syndrome
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Type I OI
- splice site mutation resulting in mRNA not being made properly, premature stop codon, etc.
- Usually there’s no mutation of glycine
- Collagen that is formed is ok, there’s less of it though
- least severe
- presents in infancy or early childhood
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Type II-IV
- Severity: II>III>IV>I
- Most mutations are substitutions in the gene for COL1A1 or COL1A2 that result in the change from Gly to another amino acid with a bulky side chain in type I collagens, preventing correct folding into the triple helix
- Fractures appear in utero for type II OI
- Dentiogenesis imperfecta too
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Common symptom in eyes of OI patients
- blue eye
- the membranes in the eye so thin
- seeing vessels underneath
- not every patient has the symptom
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Ehlers-Danlos Syndrome (EDS):
- A collection of defects
- Stretchy skin and joint hypermobility are common
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Elastin: a ______ tissue protein
-can be stretched to ________ in _____
-found in ________
-is an insoluble protein polymer synthesized from the precursor, ______
-______ genetic type
- rubbery connective
- several times their normal length
- any direction
- the walls of large arteries, lungs, and elastic ligaments
- tropoelastin
- only one
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Elastin:
-AAs composition: ________
-is secreted by cells into ______
-interacts with _____, mutations of which are responsible for ________
- rich in glycine, proline and lysine, only has a little hydroxyproline and no hydroxylysine
- extracellular space
- fibrillin
- Marfan syndrome
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Marfan syndrome is an autosomal _____ disorder that has been linked to the ___ gene on chromosome __.
The disease affects many structures, including _____, and is characterized by _______, and is believed to have affected _____.
- dominant
- FBN1
- 15
- the skeleton,lungs, eyes, heart and blood vessels
- unusually long limbs
- Abraham Lincoln
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FBN1 encodes _____, which is essential for the formation of _____ found in connective tissue.
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Without the structural support provided by fibrillin, many tissues are weakened, which can have severe consequences, for example, ________.
ruptures in the walls of major arteries
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In elastin, some lysyl side chains are ______ by ______, forming ______, ___ of which and one unmodified lysyl side chain from the same or nearby polypeptide form a _____, which helps make elastin an _______.
- oxidatively deaminated
- lysyl oxidase, Cu2+ required
- allysine residues
- three
- desmosine cross-link
- extensively interconnected rubbery network
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