BIOLOGY 2F03 Lecture Notes - Lecture 8: Adamts13, Steric Effects, Glycosylation
19 May 2018
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1. N & O linked glycosylations play important roles in the function of vWF
Importance of N Linked glycosylations (NLG) – 12sites on vWF
• Formation of vWF dimers/ multimers
o inhibition of NLG = retention of monomeric vWF in endothelial cells
• Disulphide bond formation = maintenance of globular structure of vWF
o inhiition of NLG = earl eposure of inding sites = tenden to lot
• Presenting ABO blood sugars
o inhibition of NLG = increased cleavage of ADAMTS13
Importance of O linked glycosylations (OLG) – 10sites on vWF
• OLG has a tetrsaccharide t antigen whose plasma concentration is inversely proportional to vWF
• Inhibition of vWF A1-Gp1b binding
o Inhibition of OLG = increased binding and tendency to clot
• Steric hindrance increases stability of molecule
• Protection of ADAMTS13
o Inhibition of OLG = increased clearance
• vWF without a terminal sialic acid is cleared more quickly from bloodstream because of
increased affinity to ASGRP receptor; sialic acid protects VWF against proteolysis by serine and
cysteine proteases but specifically enhances susceptibility to ADAMTS13 proteolysis
3. importance of glycosylatons in other clotting factors
• F& - has 2 N- & 2O glycosylation sites which are important for normal secretion
• F8 – glycans are important for interaction with chaperone proteins in ER
• F9 – recovery, activity, efficacy
4. importance of gamma-carboxylation
• occurs on glutamic residues of Gla domains on F2,7,9,10, Protein C/S
• the catalysing enzyme, gamma-glutamyl carboxylase is vitamin K dependent
• warfarin blocks recycling of Vit K = impaired gamma carboxylation = impaired binding of factors
to platelet phospholipids due to inability to bind calcium
1.8 – MOLECULAR MODELLING WORKSHOP
1. Why protein structures are important
SHAPE DETERMINES ACTICITY. KNOWLEDGE OF SHAPE =
• Understanding the effect of gene mutations
o Protein structures allow you to see the location of a missense mutation.
o A mutation in the core of a domain often leads to misfolding, a failure to secrete protein
from the cell and therefore low plasma level. (Type I mutations: most common)
o Some mutations cause disease because they are in a functionally important part of the
protein (Type II mutations: less common).
• Understanding how drugs affect enzymes
• Understanding research papers
• Essential tool in research
2. How protein structures are derived
find more resources at oneclass.com
find more resources at oneclass.com
Document Summary
N & o linked glycosylations play important roles in the function of vwf. Importance of o linked glycosylations (olg) 10sites on vwf: olg has a tetrsaccharide t antigen whose plasma concentration is inversely proportional to vwf. Inhibition of olg = increased binding and tendency to clot: steric hindrance increases stability of molecule, protection of adamts13. 1. 8 molecular modelling workshop: why protein structures are important. 4 types of molecular graphics: ball and stick can view interior of molecules but only gives partieal view (no sense of density) Secondary structure good view of domains but no representation of surface. Spacefill good view of surface but cant see inner structure. Surface representation accurate and realistic can show charge/ surface hydrophobicity: what you need to produce your own molecular graphics, to download a structure from the pdb database and produce a graphic in pymol. 1. 9 rare coagulation disorders: coagulation disorders apart from haemophilia are very rare and are classified based on severity.
