Traffic Problems: Inherited Disease and Intracellular Trafficking Defect Dr. Paul Gissen 1 The screen versions of these slides have full details of copyright and acknowledgements 1 Traffic Problems: Inherited Disease and Intracellular Trafficking Defect Dr. Paul Gissen UCL Laboratory for Molecular Cell Biology and Great Ormond Street Hospital for Children 2 Summary • Concepts and pathways in intracellular trafficking • Disorders affecting specific trafficking steps • ARC syndrome as an example of a trafficking disorder 3 1. Protein secretion – Polypeptides synthesised in the ribosomes – Folding +/- oligomerisation in the ER – In ER proteins are packaged into transport vesicles to travel to Golgi – Post-translational modification and sorting into various routes in Golgi – Golgi to cell membrane transport via intermediate compartments 2. Endocytosis: – Internalised proteins Either recycled to the membrane Or trafficked to lysosomes Or transcytosed from basolateral to apical membrane Intracellular protein trafficking
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Traffic Problems: Inherited Disease and Intracellular Trafficking Defect
Dr. Paul Gissen
1The screen versions of these slides have full details of copyright and acknowledgements
1
Traffic Problems: Inherited Disease and Intracellular Trafficking Defect
Dr. Paul Gissen
UCL Laboratory for Molecular Cell Biology
and
Great Ormond Street Hospital for Children
2
Summary
• Concepts and pathways in intracellular trafficking
• Disorders affecting specific trafficking steps
• ARC syndrome as an example of a trafficking disorder
3
1. Protein secretion
– Polypeptides synthesised in the ribosomes
– Folding +/- oligomerisation in the ER
– In ER proteins are packaged into transport vesicles to travel to Golgi
– Post-translational modification and sorting into various routes in Golgi
– Golgi to cell membrane transport via intermediate compartments
2. Endocytosis:
– Internalised proteins
Either recycled to the membrane
Or trafficked to lysosomes
Or transcytosed from basolateral to apical membrane
Intracellular protein trafficking
Traffic Problems: Inherited Disease and Intracellular Trafficking Defect
Dr. Paul Gissen
2The screen versions of these slides have full details of copyright and acknowledgements
4
Nucleus
ER
Golgi
Lysosome
MVB
EE
LE
Intracellular vesicle traffic
5
Clinical syndromes with abnormal intracellular trafficking
• Batten’s disease/neuronal ceroid lipofuscinosis
(accumulation of protein degradation products)
• Niemann Pick type C disease (lipid trafficking defect)
• Mucolipidosis (abnormal transport
of lysosomal enzymes)
• Hermansky-Pudlak syndrome(HPS)
(abnormal biosynthesis of pigment organelles)
• Hereditary spastic paraplegias (defect in trafficking
along axons)
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Donor compartment
Acceptor compartment
Microfilaments
Molecular motors
Traffic Problems: Inherited Disease and Intracellular Trafficking Defect
Dr. Paul Gissen
3The screen versions of these slides have full details of copyright and acknowledgements
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• Romanian - US scientist
• Nobel Prize in physiology and medicine 1974
• Identification of cell structure
• Shared with Christian De Duve and Albert Claude
Mitochondria RER Golgi interface
George Palade (1912-2008)
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Membrane Interaction during secretionGolgi apparatus and protein secretion
9 Kallunki et al., Oncogene 2012
• Belgian scientist
• Nobel Prize in physiology and medicine 1974
• Identification of cell structure: lysosomes, peroxisomes
• Shared with George Palade and Albert Claude
Christian De Duve (1917-2013)
Traffic Problems: Inherited Disease and Intracellular Trafficking Defect
Dr. Paul Gissen
4The screen versions of these slides have full details of copyright and acknowledgements
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• US scientist
• 1936- (Washington University, St Louis)
• Biosynthesis, processing, and maturation of N-linked glycan chains
• Phosphorylation of N-glycans on lysosomal enzymes,
which mediates their selective targeting to lysosomes
Stuart Kornfeld
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• US scientist
• 1947- (Yale University)
• Nobel Prize in physiology and medicine 2013
with Randy Sheckman and Thomas Sudhof
• Developed in vitro assays reproducing intracellular trafficking events
• Identified and cloned the proteins that constitute membrane docking
and fusion machinery
• Introduced SNARE hypothesis
Sollner et al, 1993
James Rothman
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• US scientist 1948- (UC Berkeley)
• Nobel Prize in Physiology and medicine 2013
with James Rothman and Thomas Sudhof
• Isolated secretory (sec) mutants in yeast
• Identified genes
and established biochemical
reactions to reproduce specific
secretory pathway events
Randy Schekman
Traffic Problems: Inherited Disease and Intracellular Trafficking Defect
Dr. Paul Gissen
5The screen versions of these slides have full details of copyright and acknowledgements
13
Intracellular trafficking machinery
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Cargo recruitment and vesicle biogenesis
• Process requires multisubunit adaptor proteins e.g. AP1
• Coat proteins e.g. Clathrin, COPI, COPII
• Coats, coat-associated proteins, PIPs and Rab proteins
provide cargo specificity
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Disorders of vesicle biogenesis
• Abnormality in COPII vesicle formation
and procollagen trafficking:
– Cranio-lenticulo-sutural dysplasia: SEC23A
• Abnormal biogenesis of melanosomes
and other lysosome related organelles
– Hermansky-Pudlak Syndrome (HPS1-9)
Traffic Problems: Inherited Disease and Intracellular Trafficking Defect
Dr. Paul Gissen
6The screen versions of these slides have full details of copyright and acknowledgements
16
Defects in Rabs and Rab-associated proteins
• Rab proteins: small GTPases
• Involved in multiple steps of vesicular tafficking: