Arginine finger

In molecular biology, an arginine finger is an amino acid residue of some enzymes.[1][2] Arginine fingers are often found in the protein superfamily of AAA+ ATPases, GTPases, and dUTPases, where they assist in the catalysis of the gamma phosphate or gamma and beta phosphates from ATP or GTP, which creates a release of energy which can be used to perform cellular work.[3][1][4][2] Thus, they are essential for many forms of life, and are highly conserved.[3][1][5] Arginine fingers function through non-covalent interactions.[1] They may also assist in dimerization, and while they are found in a wide variety of enzymes, they are not ubiquitous.[6][7]

Role in catalytic mechanismsEdit

Generally, the role of the arginine finger in catalysis is to function in transition state stabilization to allow water to perform a nucleophilic attack to cleave off a number of phosphate groups.[1][7] However, there are exceptions, and arginine fingers can assist in other roles.[8][6] Additionally, arginine fingers may be attached to different subunits or other proteins in a multiprotein complex.[7] Arginine fingers sometimes interact with guanidinium during their role in catalysis.[9][7]


Arginine fingers often work with other features in their assistance of catalysis.[1] For example, in some trimeric dUTPases, such as those of M. tuberculosis, arginine fingers at the 64th and 140th residue can work with magnesium to cleave dUTP into dUMP and a pyrophosphate.[1][10] The underlying mechanism of action for this is a nucleophilic attack; the positively charged magnesium ion (Mg2+
) pulls on an oxygen of the beta and gamma phosphates to allow water to hydrolyze the bond between the beta and alpha phosphates.[1] The arginine fingers help stabilize the transition state.[1] Arginine fingers often interact with other motifs such as the Walker motifs and to perform catalysis more efficiently.[4][6][2]

Ras GTPasesEdit

Arginine fingers are also present in Ras GTPases, where they help cleave GTP to turn Ras off.[11][5] Ras is a GTPase which functions in signal transduction to regulate cell growth and division.[12][13] In addition to being positively charged, which helps arginine fingers function as a catalyst, the arginine finger in Ras displaces solvent molecules and creates an optional charge distribution.[8][13][14] Like those of dUPTases, the arginine fingers of Ras GTPases are assisted by a magnesium ion.[14] Furthermore, multiple arginine finger residues can all point towards the same point, thus focusing their effect.[15] Mutations affecting the arginine fingers of Ras lead to trouble catalyzing GTP by factors of around two to five orders of magnitude.[8][5][4][14] Thus, as Ras is an oncogene and is activated and deactivated by the hydrolysis of GTP, mutations in Ras's arginine finger residues can lead to cancer.[5][3] Glutamate also plays a role near arginine fingers and is stabilized by the arginines' backbone chain carboxyl groups, which are known as knuckles.[15]

Heterotrimeric G proteinsEdit

In heterotrimeric G proteins, catalysis of GTP can be assisted by aluminum tetrafluoride (AlF
) and RGS4.[15][3] Heterotrimeric G proteins are larger three-part proteins serve in signal transduction of many pathways.[3] The catalytic mechanism for GTP hydrolysis in heterotrimeric G proteins consists of an active state where catalysis is likely to occur and an inactive state where catalysis is unlikely.[3] In the active state, AlF
stabilizes the transition state and points the arginine finger residue towards GTP.[3] This causes increased charge density on the beta phosphate of GTP and planarization of the gamma phosphate, which creates an opening and reduces steric hindrance for water to hydrolyze the phosphoanhydride beta-gamma bond.[3] This is because the gamma phosphate's bond to the beta phosphate bends, exposing its connection and allowing the subsequent nucleophilic substitution reaction initiated by water.[3] The complex formed with RGS4 assists in this process by creating strain on the bond between the gamma and beta phosphates and assisting in distributing more charge onto the beta phosphate.[3]

ATP synthaseEdit

ATP synthase consists of a F1 and F0 subunit.[9] The F1 subunit contains alpha and beta subunits of its own which can assist in the formation of ATP, or hydrolyze it to serve as a proton pump.[16] Though most catalytic actions happen on the beta subunits, the alpha subunits each contain an arginine finger.[9] The role of the arginine finger in ATP synthase is akin to the function of the arginine finger residues of G proteins; to help split ATP.[9] For example, if the arginine of the arginine finger is substituted by lysine, possibly due to a missense mutation, the αR364K mutant results.[9] In the αR364K mutant, the ability of ATP synthase to hydrolyze ATP is decreased around a thousandfold compared to the wild type.[9]

RecQ helicaseEdit

A RecQ helicase is one of a family of helicases that helps reduce sister chromatid exchange during meiosis to lower mutation rates.[17][7] RecQ helicases are found in many organisms, ranging from E. coli to humans.[17][7] One of these helicases, the Bloom syndrome protein, contains an arginine finger which assists in its hydrolysis of ATP.[7] In humans, the arginine finger of the Bloom syndrome protein is Arg982.[7] The RecQ helicase, along with most proteins containing arginine fingers, is inhibited by sodium orthovanadate, which interferes with the arginien finger residue.[7]


  1. ^ a b c d e f g h i Nagy, Gergely N.; Suardíaz, Reynier; Lopata, Anna; Ozohanics, Olivér; Vékey, Károly; Brooks, Bernard R.; Leveles, Ibolya; Tóth, Judit; Vértessy, Beata G.; Rosta, Edina (Nov 16, 2016). "Structural Characterization of Arginine Fingers: Identification of an Arginine Finger for the Pyrophosphatase dUTPases". Journal of the American Chemical Society. 138 (45): 15035–15045. doi:10.1021/jacs.6b09012. ISSN 0002-7863. PMID 27740761.
  2. ^ a b c Chen, Baoyu; Sysoeva, Tatyana A.; Chowdhury, Saikat; Guo, Liang; De Carlo, Sacha; Hanson, Jeffrey A.; Yang, Haw; Nixon, B. Tracy (2010-11-10). "Engagement of Arginine Finger to ATP Triggers Large Conformational Changes in NtrC1 AAA+ ATPase For Remodeling Bacterial RNA Polymerase". Structure. 18 (11): 1420–1430. doi:10.1016/j.str.2010.08.018. ISSN 0969-2126. PMC 3001195. PMID 21070941.
  3. ^ a b c d e f g h i j Mann, Daniel; Teuber, Christian; Tennigkeit, Stefan A.; Schröter, Grit; Gerwert, Klaus; Kötting, Carsten (2016-12-13). "Mechanism of the intrinsic arginine finger in heterotrimeric G proteins". Proceedings of the National Academy of Sciences. 113 (50): E8041–E8050. doi:10.1073/pnas.1612394113. ISSN 0027-8424. PMC 5167181. PMID 27911799.
  4. ^ a b c Wendler, Petra; Ciniawsky, Susanne; Kock, Malte; Kube, Sebastian (2012-01-01). "Structure and function of the AAA+ nucleotide binding pocket". Biochimica et Biophysica Acta (BBA) - Molecular Cell Research. AAA ATPases: structure and function. 1823 (1): 2–14. doi:10.1016/j.bbamcr.2011.06.014. ISSN 0167-4889. PMID 21839118.
  5. ^ a b c d Bourne, Henry R. (Oct 1997). "The arginine finger strikes again". Nature. 389 (6652): 673–674. doi:10.1038/39470. ISSN 1476-4687. PMID 9338774. S2CID 31041807.
  6. ^ a b c Zhao, Zhengyi; De-Donatis, Gian Marco; Schwartz, Chad; Fang, Huaming; Li, Jingyuan; Guo, Peixuan (2016-10-01). "An Arginine Finger Regulates the Sequential Action of Asymmetrical Hexameric ATPase in the Double-Stranded DNA Translocation Motor". Molecular and Cellular Biology. 36 (19): 2514–2523. doi:10.1128/MCB.00142-16. ISSN 0270-7306. PMC 5021374. PMID 27457616.
  7. ^ a b c d e f g h i Ren, Hua; Dou, Shuo-Xing; Rigolet, Pascal; Yang, Ye; Wang, Peng-Ye; Amor-Gueret, Mounira; Xi, Xu Guang (2007-09-15). "The arginine finger of the Bloom syndrome protein: its structural organization and its role in energy coupling". Nucleic Acids Research. 35 (18): 6029–6041. doi:10.1093/nar/gkm544. ISSN 0305-1048. PMC 2094072. PMID 17766252.
  8. ^ a b c te Heesen, Henrik; Gerwert, Klaus; Schlitter, Jürgen (2007-12-11). "Role of the arginine finger in Ras·RasGAP revealed by QM/MM calculations". FEBS Letters. 581 (29): 5677–5684. doi:10.1016/j.febslet.2007.11.026. ISSN 0014-5793. PMID 18022389. S2CID 30116707.
  9. ^ a b c d e f Komoriya, Yoshihito; Ariga, Takayuki; Iino, Ryota; Imamura, Hiromi; Okuno, Daichi; Noji, Hiroyuki (2012-04-27). "Principal Role of the Arginine Finger in Rotary Catalysis of F1-ATPase". The Journal of Biological Chemistry. 287 (18): 15134–15142. doi:10.1074/jbc.M111.328153. ISSN 0021-9258. PMC 3340237. PMID 22403407.
  10. ^ Harris, Jonathan M; McIntosh, Evan M; Muscat, George E. O (1999-04-30). "Structure/function analysis of a dUTPase: catalytic mechanism of a potential chemotherapeutic target11Edited by M. Yaniv". Journal of Molecular Biology. 288 (2): 275–287. doi:10.1006/jmbi.1999.2680. ISSN 0022-2836. PMID 10329142.
  11. ^ Kötting, Carsten; Kallenbach, Angela; Suveyzdis, Yan; Wittinghofer, Alfred; Gerwert, Klaus (2008-04-29). "The GAP arginine finger movement into the catalytic site of Ras increases the activation entropy". Proceedings of the National Academy of Sciences. 105 (17): 6260–6265. Bibcode:2008PNAS..105.6260K. doi:10.1073/pnas.0712095105. ISSN 0027-8424. PMC 2359817. PMID 18434546.
  12. ^ Lu, Shaoyong; Jang, Hyunbum; Gu, Shuo; Zhang, Jian; Nussinov, Ruth (2016-09-21). "Drugging Ras GTPase: A comprehensive mechanistic and signaling structural view". Chemical Society Reviews. 45 (18): 4929–4952. doi:10.1039/c5cs00911a. ISSN 0306-0012. PMC 5021603. PMID 27396271.
  13. ^ a b Rehmann, Holger; Bos, Johannes L. (May 2004). "Thumbs up for inactivation". Nature. 429 (6988): 138–139. doi:10.1038/429138a. ISSN 1476-4687. PMID 15141193. S2CID 28866434.
  14. ^ a b c Gerwert, Klaus; Mann, Daniel; Kötting, Carsten (2017-05-01). "Common mechanisms of catalysis in small and heterotrimeric GTPases and their respective GAPs". Biological Chemistry. 398 (5–6): 523–533. doi:10.1515/hsz-2016-0314. ISSN 1437-4315. PMID 28245182.
  15. ^ a b c Bourne, Henry R. (Oct 1997). "How converging fingers keep GTP in line". Nature. 389 (6652): 674. Bibcode:1997Natur.389..674B. doi:10.1038/39472. ISSN 1476-4687. S2CID 33932991.
  16. ^ Kulish, O.; Wright, A. D.; Terentjev, E. M. (2016-06-20). "F 1 rotary motor of ATP synthase is driven by the torsionally-asymmetric drive shaft". Scientific Reports. 6 (1): 28180. arXiv:1601.08078. Bibcode:2016NatSR...628180K. doi:10.1038/srep28180. ISSN 2045-2322. PMC 4913325. PMID 27321713.
  17. ^ a b Reference, Genetics Home. "BLM gene". Genetics Home Reference. Retrieved 2020-04-04.