C1519978_NCI_BioC

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?:definition	Eukaryotic cells take up constituents of the extra-cellular environment and regulate the cell-surface level of membrane proteins via a recycling system of membrane vesicles called endosomes. When cells are taking up elements from the cell-surface it is called endocytosis, and when they are delivered to the cell-surface it is called exocytosis. The transferrin receptor (TfR) is often employed as a model protein for studying this process. The transferrin receptor mediates uptake of iron by binding diferrictransferrin (Tf-2Fe++) from the plasma. Endocytosis of the receptor is initiated by the formation of a clathrin-coated pit in the cell membrane, which subsequently forms the primary endosome and then fuses with the early endosome. The lumen of an early endosome has a slightly acidic pH, which enables the ions to be released. The ions move to the cytosol and the receptor-apotransferrin (Tf) complex is sorted for recycling back to the cell membrane in recycling endosomes. At the cell surface the apotransferrin is replaced with diferrictransferrin and the cycle repeats. Whether an endocytosed protein is recycled or not is determined by a sorting process initiated in the early endosome. The early endosome is the first organelle along the endo-lysosomal pathway and it is the major sorting station. Internalized membrane proteins can either be sorted for recycling from the early endosome by a fast route (e.g., TfR) or make it to the late endosome and recycle by a slow route (e.g., angiotensin receptor, AT1R) or be retained in the late endosome and directed to the lysosome for degradation (e.g., epidermal growth factor receptor, EGFR). The early endosome has been suggested to turn into a multi-vesicular late endosome through a maturation process that changes its biochemical composition and morphology. The late endosome is followed by the lysosome, which is the terminal organelle on the endocytic pathway and is devoid of recycling receptors. The lysosome has a very acidic environment and contains proteases. Vesicular trafficking and proper sorting of internalized proteins require the recruitment of cytosolic proteins to a specific endosomal membrane in a reversible and regulated manner. Many proteins become reversibly localized to membranes through interaction with specific lipid head groups. Phosphatidylinositol 3-phosphate (PI3P) is a minor PI3K product that is constitutively produced and specifically localize to early endosomes and several proteins bind specifically to its head group. These proteins all have a domain called a FYVE-finger which binds to PI3P. It is a cysteine-rich domain reminiscent of a zinc finger with eight conserved cysteines, which coordinate two Zinc ions, and several other conserved residues. Two FYVE finger proteins important in vesicle transport are illustrated in this pathway. The first and most well studied is the early endosomal autoantigen (EEA1). It is a protein involved in fusion of primary endosomes with early endosomes. EEA1 is a large coiled-coil protein that contains a C-terminal FYVE-finger and two domains that bind to the active, GTP-bound form of the early-endosomal GTPase Rab5. One of these domains is adjacent to the FYVE-finger, whereas the other, a C2H2-type zinc finger, is found at the N terminus. The C terminus of EEA1, containing one Rab5-binding domain and the FYVE-finger, is necessary and sufficient for specific targeting of EEA1 to early endosomes, and the membrane binding requires both PI3K activity and Rab5:GTP. The relatively low affinities of the C-terminal Rab5-binding domain for Rab5:GTP and of the FYVE-finger for PI3P secure that under physiological conditions, EEA1 is only recruited to membranes that contain both of these components and Rab5 is required on both membranes in order for the fusion to take place. The second FYVE finger protein in this pathway is HRS. It is also present in early endosomal membranes and is involved in sorting of endocytosed proteins. It binds ubiquitinated proteins and sorts them into clathrin-coated microdomains of the early endosomes. HRS has a domain structure with a FYVE domain, an N-terminal VHS-domain, an ubiquitin interacting motif (UIM), a proline-rich domain, two coiled-coil domains (the second binds to the SNARE protein SNAP-25), and a C-terminal clathrin interacting domain. There are two different forms of clathrin coats in endosomes with distinct localization, one that is involved in budding to form recycling vesicles and one with a flat morphology. HRS binds to the flat clathrin, which causes its specific localization in these parts of the early endosome. HRS prevents receptor recycling by recruiting and concentrating ubiquitinated proteins such as the EGFR in the early endosomes. The ubiquitinated proteins are retained in the late endosome and polyubiquitinated proteins are subsequently transported to the lysosome for degradation. (This definition may be outdated - see the DesignNote.)
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?:definition

Eukaryotic cells take up constituents of the extra-cellular environment and regulate the cell-surface level of membrane proteins via a recycling system of membrane vesicles called endosomes. When cells are taking up elements from the cell-surface it is called endocytosis, and when they are delivered to the cell-surface it is called exocytosis. The transferrin receptor (TfR) is often employed as a model protein for studying this process. The transferrin receptor mediates uptake of iron by binding diferrictransferrin (Tf-2Fe++) from the plasma. Endocytosis of the receptor is initiated by the formation of a clathrin-coated pit in the cell membrane, which subsequently forms the primary endosome and then fuses with the early endosome. The lumen of an early endosome has a slightly acidic pH, which enables the ions to be released. The ions move to the cytosol and the receptor-apotransferrin (Tf) complex is sorted for recycling back to the cell membrane in recycling endosomes. At the cell surface the apotransferrin is replaced with diferrictransferrin and the cycle repeats. Whether an endocytosed protein is recycled or not is determined by a sorting process initiated in the early endosome. The early endosome is the first organelle along the endo-lysosomal pathway and it is the major sorting station. Internalized membrane proteins can either be sorted for recycling from the early endosome by a fast route (e.g., TfR) or make it to the late endosome and recycle by a slow route (e.g., angiotensin receptor, AT1R) or be retained in the late endosome and directed to the lysosome for degradation (e.g., epidermal growth factor receptor, EGFR). The early endosome has been suggested to turn into a multi-vesicular late endosome through a maturation process that changes its biochemical composition and morphology. The late endosome is followed by the lysosome, which is the terminal organelle on the endocytic pathway and is devoid of recycling receptors. The lysosome has a very acidic environment and contains proteases. Vesicular trafficking and proper sorting of internalized proteins require the recruitment of cytosolic proteins to a specific endosomal membrane in a reversible and regulated manner. Many proteins become reversibly localized to membranes through interaction with specific lipid head groups. Phosphatidylinositol 3-phosphate (PI3P) is a minor PI3K product that is constitutively produced and specifically localize to early endosomes and several proteins bind specifically to its head group. These proteins all have a domain called a FYVE-finger which binds to PI3P. It is a cysteine-rich domain reminiscent of a zinc finger with eight conserved cysteines, which coordinate two Zinc ions, and several other conserved residues. Two FYVE finger proteins important in vesicle transport are illustrated in this pathway. The first and most well studied is the early endosomal autoantigen (EEA1). It is a protein involved in fusion of primary endosomes with early endosomes. EEA1 is a large coiled-coil protein that contains a C-terminal FYVE-finger and two domains that bind to the active, GTP-bound form of the early-endosomal GTPase Rab5. One of these domains is adjacent to the FYVE-finger, whereas the other, a C2H2-type zinc finger, is found at the N terminus. The C terminus of EEA1, containing one Rab5-binding domain and the FYVE-finger, is necessary and sufficient for specific targeting of EEA1 to early endosomes, and the membrane binding requires both PI3K activity and Rab5:GTP. The relatively low affinities of the C-terminal Rab5-binding domain for Rab5:GTP and of the FYVE-finger for PI3P secure that under physiological conditions, EEA1 is only recruited to membranes that contain both of these components and Rab5 is required on both membranes in order for the fusion to take place. The second FYVE finger protein in this pathway is HRS. It is also present in early endosomal membranes and is involved in sorting of endocytosed proteins. It binds ubiquitinated proteins and sorts them into clathrin-coated microdomains of the early endosomes. HRS has a domain structure with a FYVE domain, an N-terminal VHS-domain, an ubiquitin interacting motif (UIM), a proline-rich domain, two coiled-coil domains (the second binds to the SNARE protein SNAP-25), and a C-terminal clathrin interacting domain. There are two different forms of clathrin coats in endosomes with distinct localization, one that is involved in budding to form recycling vesicles and one with a flat morphology. HRS binds to the flat clathrin, which causes its specific localization in these parts of the early endosome. HRS prevents receptor recycling by recruiting and concentrating ubiquitinated proteins such as the EGFR in the early endosomes. The ubiquitinated proteins are retained in the late endosome and polyubiquitinated proteins are subsequently transported to the lysosome for degradation. (This definition may be outdated - see the DesignNote.)

?:hasCUIAnnotation