RVxP motif

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RVxP motif is a protein motif involved in localizing proteins into cilia.

Cilia are sensory organelle of cells, whose malfunction can cause diseases such as polycystic kidney disease,[1] nephronophthisis and Bardet-Biedl syndrome. Proteins employed in the cilia are targeted there when they bear specific entry signals, whereas proteins not situated in cilia are removed or prevented from entering the organelles.[2] Entry signals have been found in ciliary/flagellar proteins of the protozoans Leishmania and Trypanosoma.[3]

The RVxP motif was first described for the PKD2 protein[4] and when inserted in the transferrin receptor it can target it to cilia.[5] It probably carries out its signal function through protein interactions[3] although the exact process[6] and where in the cell it takes place are unknown.[7] Three candidate proteins involved in "receiving" this signal are pericentrin at the basal body of cilia, intraflagellar transport proteins such as IFT57[3] and ARF4[8] while the BBSome does not appear to interact with the sequence.[9] The kinesins KIF17 is implicated in transporting the CNGB1 protein which has a RVxP motif into human cilia,[4] as is Rab8a in transporting PKD2.[5] Not all ciliary proteins use a RVxP motif for transport, however;[10] VxPx and Ax(S/A)xQ have also been described as cilium-targeting motifs.[6]

Examples of proteins with RVxP motifs associated with cilia:

  • Mouse Ahi1, the homologue of human AHI1, fails to localize to cilia if its RVxP sequence is mutated.[11]
  • Caenorhabditis elegans Arl13b requires a RVxP motif to localize to cilia,[12] a property shared by human ARL13B[13] but in the latter case a coiled-coil domain is also needed.[14]
  • Human ATP1A4 has a motif similar to RVxP that may play a role in localizing the protein to sperm flagella. This sequence is conserved among species.[15]
  • Human CNGB1 features a C-terminal RVxP motif at amino acids 821-824 which if mutated causes the protein to not reach the cilia; other factors however are also needed.[4] This motif is also found in animal CNGB1 homologues.[16]
  • Human CRMP2 has a RVxP motif but it does not appear to be required for its ciliar trafficking.[17]
  • Human FAM154A has a ciliary localization sequence.[18]
  • Tetrahymena GEF1 has a ciliary localization sequence and mutating it causes the protein to no longer localize to cilia.[19]
  • Human PDGFRA has a RVxP sequence and may localize to cilia thanks to it.[20]
  • Human PKD2 trafficking into cilia has been found in vitro to rely on a N-terminal RVxP motif[21] as PKD2 mutants with alterations in this motif do not appear in cilia.[22] This motif is also found in animal PKD2 homologues[3] but not in Hydra.[23] Mutating this sequence in mice knocked out for PKD1 causes PKD2 to accumulate at the foot of the cilia.[19]

Other proteins associated with cilia for which the occurrence of a RVxP motif has been discussed are PKD1 and PSEN2.[24]


References

  1. ^ Geng et al. 2006, p. 1383.
  2. ^ Geng et al. 2006, p. 1390.
  3. ^ a b c d Geng et al. 2006, p. 1391.
  4. ^ a b c Jenkins et al. 2006, p. 1211.
  5. ^ a b Hoffmeister et al. 2011, p. 641.
  6. ^ a b Dishinger, John F.; Kee, Hooi Lynn; Jenkins, Paul M.; Fan, Shuling; Hurd, Toby W.; Hammond, Jennetta W.; Truong, Yen Nhu-Thi; Margolis, Ben; Martens, Jeffrey R.; Verhey, Kristen J. (July 2010). "Ciliary entry of the kinesin-2 motor KIF17 is regulated by importin-β2 and RanGTP". Nature Cell Biology. 12 (7): 709. doi:10.1038/ncb2073. ISSN 1476-4679. PMC 2896429. PMID 20526328.
  7. ^ Hoffmeister et al. 2011, p. 642.
  8. ^ Ward, Heather H.; Brown-Glaberman, Ursa; Wang, Jing; Morita, Yoshiko; Alper, Seth L.; Bedrick, Edward J.; Gattone, Vincent H.; Deretic, Dusanka; Wandinger-Ness, Angela (20 July 2011). "A conserved signal and GTPase complex are required for the ciliary transport of polycystin-1". Molecular Biology of the Cell. 22 (18): 3298. doi:10.1091/mbc.e11-01-0082. ISSN 1059-1524. PMC 3172256. PMID 21775626.
  9. ^ Wingfield, Jenna L.; Lechtreck, Karl-Ferdinand; Lorentzen, Esben (2018-12-07). "Trafficking of ciliary membrane proteins by the intraflagellar transport/BBSome machinery". Essays in Biochemistry. 62 (6): 753–763. doi:10.1042/EBC20180030. ISSN 0071-1365. PMC 6737936. PMID 30287585.
  10. ^ Yoder, Bradley K. (1 May 2007). "Role of Primary Cilia in the Pathogenesis of Polycystic Kidney Disease". Journal of the American Society of Nephrology. 18 (5): 1383. doi:10.1681/ASN.2006111215. ISSN 1046-6673. PMID 17429051.
  11. ^ Lancaster, Madeline A.; Schroth, Jana; Gleeson, Joseph G. (June 2011). "Subcellular spatial regulation of canonical Wnt signalling at the primary cilium". Nature Cell Biology. 13 (6): 703. doi:10.1038/ncb2259. ISSN 1476-4679. PMC 3107376. PMID 21602792.
  12. ^ Blacque, O.; Cevik, S.; Clarke, L.; Van Wijk, E.; Sanders, A.; Van Reeuwijk, J.; Boldt, K.; Ueffing, M.; Roepman, R.; Kremer, H. (16 November 2012). "Differential requirements of ciliogenic/ciliopathy module components in restricting Joubert syndrome-associated Arl13b to a C. elegans Inv-like ciliary compartment". Cilia. 1 (1): O8. doi:10.1186/2046-2530-1-S1-O8. ISSN 2046-2530. PMC 3555713.
  13. ^ Nozaki, Shohei; Katoh, Yohei; Terada, Masaya; Michisaka, Saki; Funabashi, Teruki; Takahashi, Senye; Kontani, Kenji; Nakayama, Kazuhisa (1 February 2017). "Regulation of ciliary retrograde protein trafficking by the Joubert syndrome proteins ARL13B and INPP5E". Journal of Cell Science. 130 (3): 563–576. doi:10.1242/jcs.197004. ISSN 0021-9533. PMID 27927754.
  14. ^ Revenkova, Ekaterina; Liu, Qing; Gusella, G. Luca; Iomini, Carlo (1 May 2018). "The Joubert syndrome protein ARL13B binds tubulin to maintain uniform distribution of proteins along the ciliary membrane". Journal of Cell Science. 131 (9): 3. doi:10.1242/jcs.212324. ISSN 0021-9533. PMC 5992585. PMID 29592971.
  15. ^ Laird, Joseph G.; Pan, Yuan; Modestou, Modestos; Yamaguchi, David M.; Song, Hongman; Sokolov, Maxim; Baker, Sheila A. (December 2015). "Identification of a VxP Targeting Signal in the Flagellar Na /K -ATPase". Traffic. 16 (12): 1249. doi:10.1111/tra.12332. PMC 4715669. PMID 26373354.
  16. ^ Jenkins et al. 2006, p. 1213.
  17. ^ Ou, Young; Zhang, Ying; Cheng, Min; Rattner, Jerome B.; Dobrinski, Ina; van der Hoorn, Frans A. (2012-11-21). "Targeting of CRMP-2 to the Primary Cilium Is Modulated by GSK-3β". PLOS ONE. 7 (11): e48773. Bibcode:2012PLoSO...748773O. doi:10.1371/journal.pone.0048773. ISSN 1932-6203. PMC 3504062. PMID 23185275.
  18. ^ Dacheux, Denis; Roger, Benoit; Bosc, Christophe; Landrein, Nicolas; Roche, Emmanuel; Chansel, Lucie; Trian, Thomas; Andrieux, Annie; Papaxanthos-Roche, Aline; Marthan, Roger; Robinson, Derrick R.; Bonhivers, Mélanie (1 April 2015). "Human FAM154A (SAXO1) is a microtubule-stabilizing protein specific to cilia and related structures". Journal of Cell Science. 128 (7): 1295. doi:10.1242/jcs.155143. ISSN 0021-9533. PMID 25673876.
  19. ^ a b Bell, Aaron J.; Guerra, Charles; Phung, Vincent; Nair, Saraswathy; Seetharam, Raviraja; Satir, Peter (August 2009). "GEF1 is a Ciliary Sec7 GEF of Tetrahymena thermophila". Cell Motility and the Cytoskeleton. 66 (8): 483–499. doi:10.1002/cm.20348. ISSN 0886-1544. PMC 2767173. PMID 19267341.
  20. ^ Christensen, Søren T.; Pedersen, Stine F.; Satir, Peter; Veland, Iben R.; Schneider, Linda (1 January 2008). "Chapter 10 The Primary Cilium Coordinates Signaling Pathways in Cell Cycle Control and Migration During Development and Tissue Repair". Current Topics in Developmental Biology. 85. Academic Press: 271. doi:10.1016/S0070-2153(08)00810-7. ISBN 978-0-12-374453-1.
  21. ^ Geng et al. 2006, p. 1389.
  22. ^ Geng et al. 2006, p. 1393.
  23. ^ McLaughlin, Susan (11 January 2017). "Evidence that polycystins are involved in Hydra cnidocyte discharge". Invertebrate Neuroscience. 17 (1): 4. doi:10.1007/s10158-016-0194-3. ISSN 1439-1104. PMID 28078622. S2CID 3674409.
  24. ^ Pearring, Jillian N.; Agustin, Jovenal T. San; Lobanova, Ekaterina S.; Gabriel, Christopher J.; Lieu, Eric C.; Monis, William J.; Stuck, Michael W.; Strittmatter, Lara; Jaber, Samer M.; Arshavsky, Vadim Y.; Pazour, Gregory J. (14 April 2017). "Loss of Arf4 causes severe degeneration of the exocrine pancreas but not cystic kidney disease or retinal degeneration". PLOS Genetics. 13 (4): 2. doi:10.1371/journal.pgen.1006740. ISSN 1553-7404. PMC 5409180. PMID 28410364.

Sources

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