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Structures of RabGGTase-substrate/product complexes provide insights into the evolution of protein prenylation.

Guo Z, Wu YW, Das D, Delon C, Cramer J, Yu S, Thuns S, Lupilova N, Waldmann H, Brunsveld L, Goody RS, Alexandrov K, Blankenfeldt W
EMBO J 27 2444-56 (2008)
Related entries: 3dss, 3dst, 3dsu, 3dsv, 3dsw

Cited: 40 times
EuropePMC logo PMID: 18756270

Abstract

Post-translational isoprenylation of proteins is carried out by three related enzymes: farnesyltransferase, geranylgeranyl transferase-I, and Rab geranylgeranyl transferase (RabGGTase). Despite the fact that the last one is responsible for the largest number of individual protein prenylation events in the cell, no structural information is available on its interaction with substrates and products. Here, we present structural and biophysical analyses of RabGGTase in complex with phosphoisoprenoids as well as with the prenylated peptides that mimic the C terminus of Rab7 GTPase. The data demonstrate that, unlike other protein prenyl transferases, both RabGGTase and its substrate RabGTPases completely 'outsource' their specificity for each other to an accessory subunit, the Rab escort protein (REP). REP mediates the placement of the C terminus of RabGTPase into the active site of RabGGTase through a series protein-protein interactions of decreasing strength and selectivity. This arrangement enables RabGGTase to prenylate any cysteine-containing sequence. On the basis of our structural and thermodynamic data, we propose that RabGGTase has evolved from a GGTase-I-like molecule that 'learned' to interact with a recycling factor (GDI) that, in turn, eventually gave rise to REP.

Articles - 3dsx mentioned but not cited (2)

  1. Structures of RabGGTase-substrate/product complexes provide insights into the evolution of protein prenylation. Guo Z, Guo Z, Wu YW, Das D, Delon C, Cramer J, Yu S, Thuns S, Lupilova N, Waldmann H, Brunsveld L, Goody RS, Alexandrov K, Blankenfeldt W. EMBO J 27 2444-2456 (2008)
  2. Recognition and stabilization of geranylgeranylated human Rab5 by the GDP Dissociation Inhibitor (GDI). Edler E, Stein M. Small GTPases 10 227-242 (2019)


Reviews citing this publication (15)

  1. Protein prenylation: enzymes, therapeutics, and biotechnology applications. Palsuledesai CC, Distefano MD. ACS Chem Biol 10 51-62 (2015)
  2. Rab GTPases and their interacting protein partners: Structural insights into Rab functional diversity. Pylypenko O, Hammich H, Yu IM, Houdusse A. Small GTPases 9 22-48 (2018)
  3. Rab protein evolution and the history of the eukaryotic endomembrane system. Brighouse A, Dacks JB, Field MC. Cell Mol Life Sci 67 3449-3465 (2010)
  4. Isoprenoids and protein prenylation: implications in the pathogenesis and therapeutic intervention of Alzheimer's disease. Jeong A, Suazo KF, Wood WG, Distefano MD, Li L. Crit Rev Biochem Mol Biol 53 279-310 (2018)
  5. Expressed protein ligation: a resourceful tool to study protein structure and function. Berrade L, Camarero JA. Cell Mol Life Sci 66 3909-3922 (2009)
  6. Post translational modifications of Rab GTPases. Shinde SR, Maddika S. Small GTPases 9 49-56 (2018)
  7. Understanding and exploiting protein prenyltransferases. Nguyen UT, Goody RS, Alexandrov K. Chembiochem 11 1194-1201 (2010)
  8. Molecular and structural basis of metabolic diversity mediated by prenyldiphosphate converting enzymes. Brandt W, Bräuer L, Günnewich N, Kufka J, Rausch F, Schulze D, Schulze E, Weber R, Zakharova S, Wessjohann L. Phytochemistry 70 1758-1775 (2009)
  9. Biotechnological Applications of Protein Splicing. Sarmiento C, Camarero JA. Curr Protein Pept Sci 20 408-424 (2019)
  10. Is there a future for prenyltransferase inhibitors in cancer therapy? Holstein SA, Hohl RJ. Curr Opin Pharmacol 12 704-709 (2012)
  11. Farnesyl pyrophosphate synthase modulators: a patent review (2006 - 2010). Sun S, McKenna CE. Expert Opin Ther Pat 21 1433-1451 (2011)
  12. Recent Advances in the Development of Mammalian Geranylgeranyl Diphosphate Synthase Inhibitors. Haney SL, Wills VS, Wiemer DF, Holstein SA. Molecules 22 E886 (2017)
  13. Protein Prenyltransferases and Their Inhibitors: Structural and Functional Characterization. Marchwicka A, Kamińska D, Monirialamdari M, Błażewska KM, Gendaszewska-Darmach E. Int J Mol Sci 23 5424 (2022)
  14. Structure, regulation and cellular functions of Rab geranylgeranyl transferase and its cellular partner Rab Escort Protein. Gutkowska M, Swiezewska E. Mol Membr Biol 29 243-256 (2012)
  15. Targeting the Isoprenoid Biosynthetic Pathway in Multiple Myeloma. Haney SL, Holstein SA. Int J Mol Sci 24 111 (2022)

Articles citing this publication (23)

  1. Protein Lipidation: Occurrence, Mechanisms, Biological Functions, and Enabling Technologies. Jiang H, Zhang X, Chen X, Aramsangtienchai P, Tong Z, Lin H. Chem Rev 118 919-988 (2018)
  2. Analysis of the eukaryotic prenylome by isoprenoid affinity tagging. Nguyen UT, Guo Z, Guo Z, Delon C, Wu Y, Deraeve C, Fränzel B, Bon RS, Blankenfeldt W, Goody RS, Waldmann H, Wolters D, Alexandrov K. Nat Chem Biol 5 227-235 (2009)
  3. Comprehensive mutation analysis (20 families) of the choroideremia gene reveals a missense variant that prevents the binding of REP1 with Rab geranylgeranyl transferase. Esposito G, De Falco F, Tinto N, Testa F, Vitagliano L, Tandurella IC, Iannone L, Rossi S, Rinaldi E, Simonelli F, Zagari A, Salvatore F. Hum Mutat 32 1460-1469 (2011)
  4. GGTase3 is a newly identified geranylgeranyltransferase targeting a ubiquitin ligase. Kuchay S, Wang H, Marzio A, Jain K, Homer H, Fehrenbacher N, Philips MR, Zheng N, Pagano M. Nat Struct Mol Biol 26 628-636 (2019)
  5. Prenyltransferase Inhibitors: Treating Human Ailments from Cancer to Parasitic Infections. Ochocki JD, Distefano MD. Medchemcomm 4 476-492 (2013)
  6. Structure of the disordered C terminus of Rab7 GTPase induced by binding to the Rab geranylgeranyl transferase catalytic complex reveals the mechanism of Rab prenylation. Wu YW, Goody RS, Abagyan R, Alexandrov K. J Biol Chem 284 13185-13192 (2009)
  7. Geranyl and neryl triazole bisphosphonates as inhibitors of geranylgeranyl diphosphate synthase. Zhou X, Ferree SD, Wills VS, Born EJ, Tong H, Wiemer DF, Holstein SA. Bioorg Med Chem 22 2791-2798 (2014)
  8. A SNARE geranylgeranyltransferase essential for the organization of the Golgi apparatus. Shirakawa R, Goto-Ito S, Goto K, Wakayama S, Kubo H, Sakata N, Trinh DA, Yamagata A, Sato Y, Masumoto H, Cheng J, Fujimoto T, Fukai S, Horiuchi H. EMBO J 39 e104120 (2020)
  9. Efficient farnesylation of an extended C-terminal C(x)3X sequence motif expands the scope of the prenylated proteome. Blanden MJ, Suazo KF, Hildebrandt ER, Hardgrove DS, Patel M, Saunders WP, Distefano MD, Schmidt WK, Hougland JL. J Biol Chem 293 2770-2785 (2018)
  10. The C. elegans rab family: identification, classification and toolkit construction. Gallegos ME, Balakrishnan S, Chandramouli P, Arora S, Azameera A, Babushekar A, Bargoma E, Bokhari A, Chava SK, Das P, Desai M, Decena D, Saramma SD, Dey B, Doss AL, Gor N, Gudiputi L, Guo C, Hande S, Jensen M, Jones S, Jones N, Jorgens D, Karamchedu P, Kamrani K, Kolora LD, Kristensen L, Kwan K, Lau H, Maharaj P, Mander N, Mangipudi K, Menakuru H, Mody V, Mohanty S, Mukkamala S, Mundra SA, Nagaraju S, Narayanaswamy R, Ndungu-Case C, Noorbakhsh M, Patel J, Patel P, Pendem SV, Ponakala A, Rath M, Robles MC, Rokkam D, Roth C, Sasidharan P, Shah S, Tandon S, Suprai J, Truong TQ, Uthayaruban R, Varma A, Ved U, Wang Z, Yu Z. PLoS One 7 e49387 (2012)
  11. Synthesis and characterization of novel phosphonocarboxylate inhibitors of RGGT. Coxon FP, Joachimiak L, Najumudeen AK, Breen G, Gmach J, Oetken-Lindholm C, Way R, Dunford JE, Abankwa D, Błażewska KM. Eur J Med Chem 84 77-89 (2014)
  12. Flexible and general synthesis of functionalized phosphoisoprenoids for the study of prenylation in vivo and in vitro. Das D, Tnimov Z, Nguyen UT, Thimmaiah G, Lo H, Abankwa D, Wu Y, Goody RS, Waldmann H, Alexandrov K. Chembiochem 13 674-683 (2012)
  13. Rab geranylgeranyl transferase β subunit is essential for male fertility and tip growth in Arabidopsis. Gutkowska M, Wnuk M, Nowakowska J, Lichocka M, Stronkowski MM, Swiezewska E. J Exp Bot 66 213-224 (2015)
  14. Liposome reconstitution and modulation of recombinant prenylated human Rac1 by GEFs, GDI1 and Pak1. Zhang SC, Gremer L, Heise H, Janning P, Shymanets A, Cirstea IC, Krause E, Nürnberg B, Ahmadian MR. PLoS One 9 e102425 (2014)
  15. Synthesis, properties, and applications of diazotrifluropropanoyl-containing photoactive analogs of farnesyl diphosphate containing modified linkages for enhanced stability. Hovlid ML, Edelstein RL, Henry O, Ochocki J, DeGraw A, Lenevich S, Talbot T, Young VG, Hruza AW, Lopez-Gallego F, Labello NP, Strickland CL, Schmidt-Dannert C, Distefano MD. Chem Biol Drug Des 75 51-67 (2010)
  16. Unraveling receptor stoichiometry using bret. Felce JH, Davis SJ. Front Endocrinol (Lausanne) 3 86 (2012)
  17. Arabidopsis Rab Geranylgeranyltransferases Demonstrate Redundancy and Broad Substrate Specificity in Vitro. Shi W, Zeng Q, Kunkel BN, Running MP. J Biol Chem 291 1398-1410 (2016)
  18. Semisynthesis of prenylated Rab GTPases by click ligation. Yi L, Abootorabi M, Wu YW. Chembiochem 12 2413-2417 (2011)
  19. Crystals and Fatty Acid Abnormalities Are Not Present in Circulating Cells From Choroideremia Patients. Radziwon A, Cho WJ, Szkotak A, Suh M, MacDonald IM. Invest Ophthalmol Vis Sci 59 4464-4470 (2018)
  20. Impact of C-terminal truncations in the Arabidopsis Rab escort protein (REP) on REP-Rab interaction and plant fertility. Gutkowska M, Kaus-Drobek M, Hoffman-Sommer M, Małgorzata Pamuła M, Daria Leja A, Perycz M, Lichocka M, Witek A, Wojtas M, Dadlez M, Swiezewska E, Surmacz L. Plant J 108 1400-1421 (2021)
  21. Molecular Dynamics of Rab7::REP1::GGTase-II Ternary Complex and Identification of Their Putative Drug Binding Sites. Sindhu M, Saini V, Piplani S, Kumar A. Indian J Pharm Sci 75 23-30 (2013)
  22. A Novel Hypothesis on Choroideremia-Manifesting Female Carriers: Could CHM In-Frame Variants Exert a Dominant Negative Effect? A Case Report. Di Giosaffatte N, Valiante M, Tricarico S, Parise G, De Negri AM, Ricciotti G, Florean L, Paiardini A, Bottillo I, Grammatico P. Genes (Basel) 13 1268 (2022)
  23. Protective effects of intrathecal injection of AAV9-RabGGTB-GFP+ in SOD1G93A mice. Gao T, Huo J, Xin C, Yang J, Liu Q, Dong H, Li R, Liu Y. Front Aging Neurosci 15 1092607 (2023)


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