Show simple item record

dc.contributor.advisorSkehel, Paul
dc.contributor.advisorCousin, Mike
dc.contributor.authorGerondopoulos, Andreas
dc.date.accessioned2022-03-01T11:51:53Z
dc.date.available2022-03-01T11:51:53Z
dc.date.issued2022-03-01
dc.identifier.urihttps://hdl.handle.net/1842/38642
dc.identifier.urihttp://dx.doi.org/10.7488/era/1905
dc.description.abstractEukaryotic cells are subdivided into organelles with unique physicochemical compositions and functions. Establishment and maintenance of these organelles requires selective exchange of material by vesicle trafficking. Transport vesicles are formed by cytoplasmic coat protein complexes which shape the membrane, and play a further role in the selection of transmembrane cargo proteins. Transmembrane cargo receptors select cargo in the luminal compartment and bind to these coat proteins through signals in their cytoplasmic domains. Once formed, vesicles recognise and fuse with a target organelle to deliver their content. This final process is tightly regulated by small GTPases of the Rab superfamily. Here, I will describe my work investigating the role of specific Rab GTPase pathways and the KDEL cargo receptor in trafficking in the secretory and endocytic pathways in mammalian cells. There are over 60 Rabs in human cells, each of which is activated by a specific GDP-GTP exchange factor (GEF) and inactivated by a GTPase-activating protein (GAP) at a defined membrane location. For many of these Rabs the GEF and GAP were unknown at the outset of this work in which I have identified and characterised two structurally related families of Rab GEFs, the DENN and tri-longin domain proteins. The DENN family, expressed only in metazoans, which has 17 members acting on 10 different Rabs. The tri-longin family, comprises 3 heterodimeric GEF complexes: Mon1-Ccz1 for the late endosomal, lysosomal Rab7, Hps1-Hps4 (BLOC-3) which activates Rab32/Rab38 in melanogenesis and Intu-Fuz, part of CPLANE complex, which activates Rab23 at cilia. Additionally, I have shown that the unrelated Rab3GAP complex is a GEF for the ancestral Rab18 regulating the structure of the endoplasmic reticulum. In the final part of this work, I have explored how the integrity of the early secretory system depends on selective export and retrieval of proteins between the ER and the Golgi. An essential component of this system is the transmembrane cargo receptor for KDEL retrieval signals. Here I describe the structure of the KDEL receptor and mechanism by which KDEL cargo binding triggers a conformational change exposing a signal for the COP I vesicle coat.en
dc.language.isoenen
dc.publisherThe University of Edinburghen
dc.relation.hasversionBrauer, P., J. L. Parker, A. Gerondopoulos, I. Zimmermann, M. A. Seeger, F. A. Barr and S. Newstead (2019). "Structural basis for pH-dependent retrieval of ER proteins from the Golgi by the KDEL receptor." Science 363(6431): 1103-1107 doi: https://doi.org/10.1126/science.aaw2859.en
dc.relation.hasversionCabrera, M., M. Nordmann, A. Perz, D. Schmedt, A. Gerondopoulos, F. Barr, J. Piehler, S. Engelbrecht-Vandre and C. Ungermann (2014). "The Mon1-Ccz1 GEF activates the Rab7 GTPase Ypt7 via a longin-fold-Rab interface and association with PI3P-positive membranes." J Cell Sci 127(Pt 5): 1043-1051 doi: https://doi.org/10.1242/jcs.140921.en
dc.relation.hasversionGerondopoulos, A., L. Langemeyer, J. R. Liang, A. Linford and F. A. Barr (2012). "BLOC-3 mutated in Hermansky-Pudlak syndrome is a Rab32/38 guanine nucleotide exchange factor." Curr Biol 22(22): 2135-2139 doi: https://doi.org/10.1016/j.cub.2012.09.020.en
dc.relation.hasversionLevine, T. P., R. D. Daniels, L. H. Wong, A. T. Gatta, A. Gerondopoulos and F. A. Barr (2013). "Discovery of new Longin and Roadblock domains that form platforms for small GTPases in Ragulator and TRAPP-II." Small GTPases 4(2): 62-69 doi: https://doi.org/10.4161/sgtp.24262en
dc.relation.hasversionLinford, A., S. Yoshimura, R. Nunes Bastos, L. Langemeyer, A. Gerondopoulos, D. J. Rigden and F. A. Barr (2012). "Rab14 and its exchange factor FAM116 link endocytic recycling and adherens junction stability in migrating cells." Dev Cell 22(5): 952-966 doi: https://doi.org/10.1016/j.devcel.2012.04.010.en
dc.relation.hasversionYoshimura, S., A. Gerondopoulos, A. Linford, D. J. Rigden and F. A. Barr (2010). "Family-wide characterization of the DENN domain Rab GDP-GTP exchange factors." J Cell Biol 191(2): 367-381 doi: https://doi.org/10.1083/jcb.201008051.en
dc.relation.hasversionGerondopoulos A, Bastos RN, Yoshimura S, Anderson R, Carpanini S, Aligianis I, Handley MT, Barr FA. 2014 Rab18 and a Rab18 GEF complex are required for normal ER structure. J. Cell Biol. 205(5):707-20 doi: https://doi.org/10.1083/jcb.201403026en
dc.relation.hasversionMarin-Valencia I, Gerondopoulos A, Zaki MS, Ben-Omran T, Almureikhi M, Demir E, Guemez-Gamboa A, Gregor A, Issa MY, Appelhof B, Roosing S, Musaev D, Rosti B, Wirth S, Stanley V, Baas F, Barr FA, Gleeson JG. 2017 Homozygous Mutations in TBC1D23 Lead to a Non-degenerative Form of Pontocerebellar Hypoplasia. Am. J. Hum. Genet. 101(3):441-450 doi: https://doi.org/10.1016/j.ajhg.2017.07.015en
dc.relation.hasversionGerondopoulos A, Strutt H, Stevenson NL, Sobajima T, Levine TP, Stephens DJ, Strutt D, Barr FA. 2019 Planar Cell Polarity Effector Proteins Inturned and Fuzzy Form a Rab23 GEF Complex. Curr Biol. 29(19): 3323- 3330 doi: https://doi.org/10.1016/j.cub.2019.07.090en
dc.subjectvesiclesen
dc.subjectKDEL receptoren
dc.subjectRabsen
dc.subjectswitch proteinsen
dc.subjectRab GTPase pathwaysen
dc.titleInvestigation of Rabs and cargo receptors as key regulators of vesicle trafficen
dc.typeThesis or Dissertationen
dc.type.qualificationlevelDoctoralen
dc.type.qualificationnamePhD(P) Doctor of Philosophy by Research Publicationsen


Files in this item

This item appears in the following Collection(s)

Show simple item record