BMS3021 Lecture Notes - Lecture 17: Cell-Mediated Immunity, Clathrin, Egf-Like Domain
30 May 2018
School
Department
Course
Professor
Week 7. Atherosclerosis and familial
hypercholesterolaemia, Familial haemophagocytic
lymphohistiocytosis (FHL), and Cystic fibrosis (CF)
ATHEROSCLEROSIS AND FAMILIAL HYPERCHOLESTEROLAEMIA
• Mutation can be cause disease by mis-localising a protein – person can still form functional
proteins but problem arises in transport
• Trafficking pathways:
1. Default export to surface
-no specific signal required
2. Regulated export to storage vesicle
-no specific signal identified
3. Targeting to lysosome
-requires specific signal
4. Import from surface (endocytosis)
-may require specific signal
• Vesicular transport:
o Proteins are transported between organelles in vesicles
o There are different types of vesicles with different destination
o Vesicle formation involves polymerisation of coat proteins
o Vesicles move along microtubules using molecular motors
o Docking and fusion of vesicles is receptor-mediated (membrane fusion)
• Steps in vesicle trafficking:
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• Endocytosis: transport from the plasma membrane to lysosomes via endosomes
Types of endocytosis:
Phagocytosis
o Ingestion of large particles
Pinocytosis
o Ingestion of small regions of plasma membrane encapsulating
extracellular fluid and solutes
o Captures soluble material from outside
o Not specific – not very efficient
Receptor-mediated
endocytosis
o Specific internalisation of macromolecules
o More specific
o Receptors that associate specifically with a vesicle
o Serves to concentrate the protein at the sites pf plasma membrane
internalisation and can increase uptake of specific protein by 1000 fold
o Receptor is often recycled to plasma membrane after release of cargo in
the early endosome
-receptor and cargo are captured as vesicle forms
Vesicle -> early endosome -> cargo dissociates from receptor -> receptors
recycled at cell surface
• Formation of endocytic vesicles:
o Most cells continuously internalise membrane and proteins from the cell surface
eg. macrophages ingest 3% of plasma membrane per minute
Spherical transport vesicle
o Form at the plasma membrane
o Encapsulates fluid, membrane and proteins
o Move into cell using specific machinery
Clathrin – mediated endocytosis
o Most common and best understood internalisation pathway
o Endocytosis begins at specialised regions (clathrin coated
pits which comprise of 2% of surface area of the cell)
o Clathrin is a structural protein that polymerises on
membrane with assistance of accessory proteins
o Polymerisation induces membrane curvature -> forms a 3D
spherical lattice
o Coated vesicles bud from plasma membrane
Clathrin sticks to electron dense region of membrane ->
membrane curves -> proteins polymerise -> change/force
change in membrane conformation -> membrane pinches off
with coat -> coat falls off once vesicle is completely detached
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• Trafficking of endocytic transport vesicles:
o Once internalised vesicles are uncoated and delivered to early endosome (sorting
organelle)
o Vesicles move from early endosome to:
1. Cell surface (recycling)
2. Opposite surface in polarised cells- transcytosis
3. Lysosomes via late endosome (broken down and used for nutrients)
• Internalisation signals:
o Driven by information carried on proteins
o Receptors may carry a signal in the cytoplasmic domain
o Signal promotes binding to adaptins which associate with clathrin
o Signals have information
• Cholesterol:
o Cholesterol is a key component of membranes and a precursor for steroid hormones and
bile acids. It can be synthesised or obtained from diet
o Liver is the centre of cholesterol biosynthesis
o Transport: Lipoproteins
Is insoluble so is transported in blood by lipoproteins
Lipoproteins contain phospholipid, FA, cholesterol and apoproteins
-insoluble materials that body wants to move around
LDL = low density lipoprotein
VLDL = very low density lipoprotein
VLDL (has cholesterol, FA, apoproteins) circulates in the blood through tissues
Lipoprotein lipase in tissues removes FA and reduce the particle density (turns
into IDL – intermediate and as it moves, structures are stripped off an eventually
converts to LDL
IDL further degrades to a particle rich in cholesterol containing a single protein
type (apoB)
LDL is used by adrenals, gonads, adipose tissue and liver
find more resources at oneclass.com
find more resources at oneclass.com
Document Summary
Atherosclerosis and familial hypercholesterolaemia, familial haemophagocytic lymphohistiocytosis (fhl), and cystic fibrosis (cf) Atherosclerosis and familial hypercholesterolaemia: mutation can be cause disease by mis-localising a protein person can still form functional proteins but problem arises in transport, trafficking pathways, default export to surface. No specific signal required: regulated export to storage vesicle. No specific signal identified: targeting to lysosome. Receptor and cargo are captured as vesicle forms. It can be synthesised or obtained from diet: liver is the centre of cholesterol biosynthesis, transport: lipoproteins. Is insoluble so is transported in blood by lipoproteins. Insoluble materials that body wants to move around. Vldl (has cholesterol, fa, apoproteins) circulates in the blood through tissues. Lipoprotein lipase in tissues removes fa and reduce the particle density (turns into idl intermediate and as it moves, structures are stripped off an eventually converts to ldl. Idl further degrades to a particle rich in cholesterol containing a single protein type (apob)
