About this Research Topic
In eukaryotes, the transport of proteins and lipids among intracellular compartments is mediated by vesicular and tubular carriers under the direction of complex protein machinery. Intracellular trafficking entails the budding, transport, tethering, and fusion of membrane carriers. This Research Topic is focused on events that take place after a vesicle is formed but before it fuses with its target membrane, and particularly on the actions of a set of proteins called tethering factors. These tethers are thought to act over long distances to bring vesicles into the vicinity of the appropriate acceptor membrane and confer additional compartmental specificity. The topic is challenging because tethering factors, to a greater extent than other components of vesicle budding/ fusion machinery, appear to be diverse.
In 1996, Suzanne Pfeffer proposed that three Rab effectors — rabaptin-5, p115/Uso1, and the exocyst complex — might function as "Velcro factors", mediating the initial attachment of a vesicle with its target membrane. Two of these Velcro factors, rabaptin and p115/Uso1, are large homodimeric coiled-coil proteins, founding members of a class of such proteins implicated in membrane tethering. The exocyst, in contrast, exemplifies the other known class of tethering factors, which is called multisubunit tethering complexes, or MTCs. The exocyst is a hetero-octamer; other MTCs, discovered subsequently, contain 3–10 subunits each and have total molecular weights ranging from 250 to 800 kDa. More recent phylogenetic and structural evidence suggest the existence of two distinct functional sub- classes of MTCs: 1) oligomeric complexes that typically act as Rab effectors (the CATCHR group that includes Dsl1 complex, Conserved Oligomeric Golgi (COG) complex, Golgi-associated retrograde protein (GARP) complex, and Exocyst), and 2) oligomeric complexes that function as guanine nucleotide exchange factors (GEFs) for Rab proteins (Transport Protein Particle TRAPP I-III complexes, HOPS and CORVET). The two types of tethering factors — coiled-coil homodimers and MTCs — are structurally unrelated but share several functional properties, including interaction with SNARE and Rab proteins. Nonetheless a plethora of important mechanistic questions awaits investigation.
Research sub- topics:
1. Coiled-Coil Tethers involved in membrane traffic
2. Multisubunit Tethering Complexes – CATCHRs and GEFs – include assembly and regulation of assembly
3. Specificity of Tethers and biophysical properties
4. Similarities and differences (structural and functional) between tethers.
5. Recruitment of Tethers to specific membranes and membrane dynamics of tethers. Interactions of Tethers with small GTPases. How are tethers regulated in time and space?
6. What do Tethers do? What’s the evidence for tethering? Bridge model of Tether function versus functional engagement with transport machinery. Are tethers coincidence detectors?
7. Interactions of Tethers with other components of trafficking machinery – who regulates who and how? Tethers and SNAREs/membrane fusion.
8. Relationship between tethers and the cytoskeleton
9. Mitotic regulation of tether functions. Tethers in cell division.
10. Tethers in development – knock-out mice and other model organisms. Regulation of tethers during development and under distinct physiological conditions
11. Tethers at organellar/membrane contact sites. Tethering of ER and mitochondria or ER and endolysosomes? Tethers in autophagy.
12. Tethers and Disease
13. Tethers in non-model organisms
14. Evolution of tethers
In 1996, Suzanne Pfeffer proposed that three Rab effectors — rabaptin-5, p115/Uso1, and the exocyst complex — might function as "Velcro factors", mediating the initial attachment of a vesicle with its target membrane. Two of these Velcro factors, rabaptin and p115/Uso1, are large homodimeric coiled-coil proteins, founding members of a class of such proteins implicated in membrane tethering. The exocyst, in contrast, exemplifies the other known class of tethering factors, which is called multisubunit tethering complexes, or MTCs. The exocyst is a hetero-octamer; other MTCs, discovered subsequently, contain 3–10 subunits each and have total molecular weights ranging from 250 to 800 kDa. More recent phylogenetic and structural evidence suggest the existence of two distinct functional sub- classes of MTCs: 1) oligomeric complexes that typically act as Rab effectors (the CATCHR group that includes Dsl1 complex, Conserved Oligomeric Golgi (COG) complex, Golgi-associated retrograde protein (GARP) complex, and Exocyst), and 2) oligomeric complexes that function as guanine nucleotide exchange factors (GEFs) for Rab proteins (Transport Protein Particle TRAPP I-III complexes, HOPS and CORVET). The two types of tethering factors — coiled-coil homodimers and MTCs — are structurally unrelated but share several functional properties, including interaction with SNARE and Rab proteins. Nonetheless a plethora of important mechanistic questions awaits investigation.
Research sub- topics:
1. Coiled-Coil Tethers involved in membrane traffic
2. Multisubunit Tethering Complexes – CATCHRs and GEFs – include assembly and regulation of assembly
3. Specificity of Tethers and biophysical properties
4. Similarities and differences (structural and functional) between tethers.
5. Recruitment of Tethers to specific membranes and membrane dynamics of tethers. Interactions of Tethers with small GTPases. How are tethers regulated in time and space?
6. What do Tethers do? What’s the evidence for tethering? Bridge model of Tether function versus functional engagement with transport machinery. Are tethers coincidence detectors?
7. Interactions of Tethers with other components of trafficking machinery – who regulates who and how? Tethers and SNAREs/membrane fusion.
8. Relationship between tethers and the cytoskeleton
9. Mitotic regulation of tether functions. Tethers in cell division.
10. Tethers in development – knock-out mice and other model organisms. Regulation of tethers during development and under distinct physiological conditions
11. Tethers at organellar/membrane contact sites. Tethering of ER and mitochondria or ER and endolysosomes? Tethers in autophagy.
12. Tethers and Disease
13. Tethers in non-model organisms
14. Evolution of tethers
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