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84 Cards in this Set

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Are proteins just proteins normally?
No; the majority of proteins contain covalently attached molecules.
What are 5 molecules commonly added to proteins?
-Ubiquitin
-Phosphate
-Carbohydrates
-ADP-ribose
-Fatty acids/lipids/choleterol
Why is ubiquitin added to proteins?
It targets proteins for degradation in proteosomes.
What does phosphate addition do to proteins?
Activates/inactivates many enzymes
What is the term for addition of carbohydrates to protein?
Glycosylation.
WHY modify proteins?
To increase the functional diversity of the limited gene pool.
How many genes are in the human genome?
~35,000
What are 2 types of hydrophilic protein modifications?
1. Oligosaccharide addition (glycosylation)
2. ADP-ribosylation
What are 2 types of hydrophobic protein modifications?
-Fatty acid addition
-Prenylation (Cholesterol addition)
Give 2 examples of physiologic conditinos associated w/ hydrophilic modification:
-ABO blood groups
-Influenza virus
What are the effects of Hydrophobic protein modification (fatty acid/prenylation)?
Membrane association - proteins can act as membrane surface molecules.
What is the definition of an oligosaccharide?
Polymer containing 2 or more monosaccharides joined by O-glycosidic linkages.
Why is glycosylation important?
It is one of the principal co- and post-translational modifications of membrane proteins, secreted proteins, and the majority of proteins made in rough ER.
What are the 2 types of glycosylation and what is the gist of each?
N-linked: glycosylation of amide N of asparagine residues
O-linked: glycosylation of hydroxy oxygen of Ser and Thr residues.
Why glycosylate proteins?
-Assist in folding
-To give stability
-Assist in cell-cell adhesion
What is the main purpose of N-glycosylation of proteins?
To assist in proper protein folding.
What is the 1st step in N-linked glycosylation?
Addition of a precursor molecule to the target protein.
What does this precursor molecule consist of?
3 Glucose
9 mannose
2 N-acetylglucosamine
What happens after addition of the precursor molecule to the protein??
The complex is taken up by the carrier molecule DOLICHOL
What is the purpose of dolichol?
To transfer the precursor-protein complex to the correct point on the protein's polypeptide chain.
What happens as the complex is transferred by Dolichol?
It is translocated into the ER lumen.
What happens in the ER lumen?
An oligosaccharide chain is attached to Asparagine.
What catalyzes the oligosacch. transfer?
Oligosaccharyl transferase
Can an oligosacch. be transferred to just any Asn?
No; must be in the tripeptide sequences Asn-X-Ser or Asn-X-Thr
What can X be?
Any amino acid except Pro
What is the sequence containing Asn called?
Glycosylation Sequon
What happens after the glycosylation reaction?
Removal of the 3 glucose molecules in the precursor component - if the protein folded correctly.
Once the protein has correctly folded what happens to the glycoprotein?
Transport to Golgi for further processing like mannose removal.
Ok that's the end of wikipedia notes
ok
Recap: what type of modification is addition of oligosaccharides to protein?
Hydrophilic
What is an oligosaccharide?
A polymer of sugar molecules containing 2 or more monosaccharides joined by O-glycosidic linkages
Of the carbs generally found in mammals, which is not usually in glycolipids/GAGs?
Mannose
Which 2 are epimers?
GalNac and Glcnac
What are the 3 predominant sugars in glycosaminoglycans?
-Xylose
-Glucaronic acid
-Iduronic acid
What is the significant feature that makes these 3 sugars good for GAGs?
They are negatively charged.
What must happen to monosaccharides before they can be added to protein?
Acitvation - to make NT sugars
What are nucleotide sugars?
Activated, hi-energy compounds
-The immediate precursors of glycoprotein/lipid synth.
Where does sugar activation occur?
In the cytoplasm - EXCEPT FOR SIALIC ACID
Where does activation of sialic acid occur?
What does it produce?
Nucleus
-Product is CMP-sialic acid
What is the actual reaction for NT sugar synthesis
NTP + Sugar 1-phosphate -> Sugar NDP + PPi
What is the actual reaction for CMP-sialic acid?
CTP + sialic acid -> CMP-sialic acid + PPi
What are 2 methods in which NT sugars can be synthesized?
-De novo
-Epimerization
What is the major in vivo source of monosaccharide components in glycoproteins and glycolipids?
GLUCOSE
What is a major requirement of NT sugar synthesis?
ENERGY - Lots of ATP
What enzymes catalyze glycosylation?
Glycosyltransferases
Where are Glycosyltransferases found?
In the membranes of the ER and Golgi body
What exactly do glycosyltransferases do?
Transfer sugar from an activated donor (NT sugar) to an acceptor target (protein or other).
What is the important characteristic of glycosyltransferases?
Their specificity for:
1. Sugar transferred
2. Substrate transferred TO
3. Type of linkage created
How many glycosyltransferases are there?
Over 300
What do the glycosyltransferases do in N-glycosylation?
Build up the oligosaccharide chain precursor molecule.
How many glycosyltransferases operate in this process?
7 - on the cytosolic face of RER.
Where does ea. take place:
-N glycosylation
-O glycosylation
N - in the RER lumen, processing in Golgi
O - in the Golgi
Where do NT sugars tend to be?
Cytosol - so they need transporters for uptake into the RER and golgi
How do glycoproteins get to their destination after synthesis?
By vesicular transport from the lumen to the cytosol.
What are the 3 major types of carbohydrate-protein linkages?
1. N-linkage btwn GlcNAc and Asn
2. O-linkage btwn GalNAc and Ser(Thr)
3. O-linkage betwn Xyl and Ser
Where are the first 2 types of linkages found?
In membrane and secretory proteins.
Where is O linkage of Xyl-Ser found?
In proteoglycans
What is the requirement of N-linked GlcNAc and Asn?
-Must be linked to the sequence Asn-X-Ser/Thr
What is the 1st step in Biosynthesis of N-linked sugars?
Preassembly of an oligosacch. chain to Dolichol phosphate.
What is dol-P?
Dolichol phosphate; a membrane isoprenoid derivative.
What is a major regulator of Dolichol phosphate synthesis?
Cholesterol metabolism; Mevalonic acid is the precursor of both dol P and cholesterol.
What is step 2 of N-glycosylation?
Translation of proteins in RER
What is step 3 of N-glycosylation?
Oligosaccharyltransferase catalyzes the co-translational transfer of precursor oligosacch. chain from dol-P to the Asn residue.
Where does the Asn residue hve to be located again?
In the sequence Asn-X-Ser/Thr
Where does step 3 occur?
in the lumen of the ER.
Where does the building up of the oligosaccharide precursor occur?
-First 7 steps (2 glu + 5 Mannoses) on RER face
-Last 7 steps (4 more mannoses + 3 Glc) IN RER lumen
So what 2 different enzyme types are needed for N-linkage?
-14 Glycosyltransferases - for making the precursor
-1 Oligosaccharyltransferase - to transfer precursor to Asn.
What happens after the actual N-linkage is made?
Vesicular transport from RER lumen to golgi for processing and further modifications.
What kind of modifications occur on the glycoproteins in golgi regions?
Chaperones recognize specific sugars and assist in specific protein folding.
Ok. Recap; where are O-glycosidic linkages between GalNAc and Ser/Thr found?
In secretory and membrane glycoproteins.
How is O-linked glycosylation different from N-linked?
-No specific sequon recogn'n.
-No preformed precursor
-No common core structure
-Not cotranslational
-Stepwise addition of sugars
-No glycosidases
Where does each function:
-Glycosidases
-Glycosyltransferases
Glycosidases - ER and golgi
Glycosyltransferses - Golgi
How is o-linked glycosylation SIMILAR to n-linked?
Both use the action of glycosyltransferases to make the oligosaccharide chain.
What 2 types of O-linkages exist again?
1. GalNAc - Ser/Thr
2. Xyl - Ser
Where are Xyl-Ser linkages found?
In Proteoglycans
What are proteoglycans?
Glycoproteins that contain a spcf type of oligosaccharide called GAGs
What are GAGs?
Glycosaminoglycans - neg charged polysaccharides made of repeating disacch. units which are sulfated.
How many GAGs are commonly found in Proteoglycans?
MANY - like 100 or more
What 4 GAGs are used in proteoglycans?
-Hyaluronic acid
-Chondroitin sulfate
-Heparin/heparin sulfate
-Dermatan sulfate
How are GAGs attached to proteoglycans?
Via covalent links - EXCEPT HYLAURONIC ACID
What is the common linkage region for the GAGs except hylauronic acid?
GlcUA-Gal-Gal-Xyl-Ser
What is the purpose of Hyaluronic acid if not covalently linked to the proteoglycan?
Serves as the backbone scaffold for proteoglycans.
What is a proteoglycan macromolecule made of?
Core - hylauronic acid
-Link proteins
-GAGs bound to core protein
What are the functions of proteoglycans?
-Bind H2O via highly neg charged sugars to support joints.