Membrane Traffic is the transport of molecules and compounds which are required in different areas of the cells.
Two of the main organelles involved in this process are the Endoplasmic Reticulum and the Golgi Apparatus.
Large numbers of machinery are needed during the transport process and without them it could not occur and as a result the cell would not function properly.
There are a number of diseases which affect this machinery along with the plasma membrane which is also involved in the process of Endocytosis and Exocytosis.
One such disease is Cranio-Lenticulo-Sutural Dysplasia (CLSD), and this causes the formation of abnormal bone and connective tissue structure. It is an Autosomal recessive disease resulting from a failing in the secretion of extracellular matrix proteins. The protein responsible for this is the SEC23A component of the COPII coat, which is used to traffic molecules from the Endoplasmic Reticulum to the Golgi Apparatus.
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It also effects the localisation of the COPII component Sec31, which is used when forming the coats around vesicles. (7)
When forming a vesicle leaving the Endoplasmic Reticulum (ER), there are several different proteins required and the process occurs in a cycle.
Firstly, a Sar1 GDP must undergo phosphorylation, forming Sar1 GTP, this occurs via the Sar1- GTP Exchange Factor (GEF) which is found embedded in the membrane of the ER. Sar1 GTP then becomes bound to the membrane and is now active.
Sec23 and 24 are then recruited. Sec 23 associates with Sar1 GTP and Sec 24 sits next to Sec23 and binds to a cargo receptor within the membrane. This receptor collects cargo from the ER which will be transported within the vesicle into the cytosol.
The next step in the process is the recruitment of Sec 13 and 31 which assemble onto the Sec23/24, Sar1 complex and bend the membrane. Further bending of the membrane will lead to the complete formation of the vesicle.
The entire coating complex is known as the COPII coat.
When the vesicle has been formed and has completely dissociated with the ER Sec23/24 GAP becomes active and causes the entire coat to fall off of the vesicle. Sec23/254 GAP is a GTPase Activating protein, so causes the dephosphorylation of Sar1 GTP to Sar1 GDP. Sar1 is the only piece of the machinery that is attached to the vesicle membrane, so the dephosphorylation of this results in the entire coat falling off the membrane.
The complex machinery is recycled back into the ER for further vesicle formation.
An individual with CLSD has defective Sec23/31 components which cannot associate with the Sar1 GTP effectively or create a stable outside coating. Therefore the entire coat is unstable and cannot function effectively.
The diagram below shows an outline for the COP II coat mechanism.
Figure 13-17 Molecular Biology of the Cell, 4th Edition. Alberts et al (2002)
Choroideremia is another disease that I would like to discuss. It is X-chromosome linked and occurs due to a defect in the gene CHM which codes for the Rab Escort Protein (REP1). (1) The disease leads to the degeneration of Choriocapillaris (a layer of capillaries found in the choroid), a retinal pigment epithelium and photoreceptor layer within the eye. (7)
REP1 is involved in the recycling of the Rab protein, which is used to direct vesicles during exdocytosis and endocytosis. It binds to unprenylated Rab GTPases and sends them to another enzyme, Rab GGtase to undergo a geranyl geranyl transfer reaction. This reaction transfers two geranylgeranyl groups to cysteine residues found at the C terminus of the protein. (2), (6)
This reaction leads to the localisation of the Rab to the target intracellular membrane.
Unprenylated Rab GTPases lack a hydrophobic region need by the protein to function correctly.
The Rab protein is involved in the translocation and binding of vesicles to the target membrane. It acts as a Lipid Anchor and assists the action of Snare proteins.(3)
Two types of Snare proteins are used in the trafficking of a vesicle. The first is V-Snare, found on the Vesicle membrane. The second is the T-Snare, which is found on the Target membrane. The V and T Snares connect by wrapping themselves around each other, bringing the vesicle closer to the target membrane, enabling the incorporation of the vesicle into the target membrane.
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Rab is found within the vesicular membrane in the inactive state, Rab GDP. It undergoes phosphorylation when activated, forming Rab GTP and then binds to a receptor on the target membrane, before to the Snare proteins undergo their function. It allows the vesicle to translocate closer to the target membrane assisting the Snares.
When the transfer is complete Rab undergoes GTP hydrolysis reforming Rab GDP. This unbinds itself from the target membrane receptor and is recycled to be used in further vesicle translocation.
Without the REP1, Rab would remain unprenylated, and would not be able to function correctly. This would therefore mean that vesicles would not be delivered to their correct location, and the cell would not receive the nutrients required.
The diagram below shows the Mechanism of the Rab protein, during Vesicle Transportation.
Figure 13-14. Molecular Biology of the Cell, 4th Edition. Alberts et al (2002)
The final disease I would like to discuss is Hermansky-Pudlak syndrome (HPS) which is a rare Autosomal recessive disease. The defect is found in Chromosome 10 and involves many subunits.
â€˜The mutation causes defective Endosome sorting specifically Melanosomes, Platelet dense granules, lamellar bodies of type II alveolar epithelial cells, T-lymphocytes and Lytic granules.
Also the leakage of lysosomal membrane proteins to the cell surface and the build up of a wax like substance called Ceriod in tissues. This causes damage, specifically found in the Liver and Kidneys.â€™ (7)
Visible symptoms of the syndrome include decreased pigmentation (oculocutaneous albinism). Also, bleeding problems can arise as a result of platelet abnormality, specifically a platelet storage pool defect and the storage of an abnormal fat-protein called Ceriod lipofuscin. (4)
The proteins involved are used to modify molecules in the Post Golgi endomembrane system which modifies protein, among other molecules before they are sent to their targets.
There are two main types of HPS, Type 1 involves 3 to 8 components involved in the biogenesis of lysosome-related organelles complex 1 to 3 (BLOC1-3) which is used for normal biogenesis.
BLOC1 is thought to be involved in self-assembly and interaction with the Actin cytoskeleton. (5)
Type 2 involves an Adaptor related protein complex 3 beta-1 subunit (AP3B1). It is caused by an immunodeficiency in its phenotype.
Any disruption of the machinery required to undergo membrane trafficking can greatly affect the naÃ¯ve cell. Each molecule has a specific role, designed exactly to the required specifications, and if they cannot carryout their functions the entire cycle can breakdown, possibly resulting in cell death.
This is not explicit to the machinery, if the membrane of the cell breaks down or becomes unstable, this will also effect the overall management of the cell.