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Small Gtpases: Structure, Biological Function and Its Interaction with Nanoparticles

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Small Gtpases: Structure, Biological Function and Its Interaction with Nanoparticles Asian Journal of Pharmaceutical Sciences 14 (2019) 30–39 Available online at www.sciencedirect.com journal homepage: www.elsevier.com/locate/AJPS Review Small GTPases: Structure, biological function and its interaction with nanoparticles Siyang Song a,b, Wenshu Cong b, Shurong Zhou b, Yujie Shi b, Wenbing Dai b, ∗ Hua Zhang b, Xueqing Wang b, Bing He b, Qiang Zhang a,b, a Shenyang Pharmaceutical University, No. 103, Wenhua Road, Shenyang 110016, China b Peking University, No. 38, Xueyuan Road, Beijing 100191, China a r t i c l e i n f o a b s t r a c t Article history: Small GTPase is a kind of GTP-binding protein commonly found in eukaryotic cells. It plays Received 11 May 2018 an important role in cytoskeletal reorganization, cell polarity, cell cycle progression, gene ex- Revised 6 June 2018 pression and many other significant events in cells, such as the interaction with foreign par- Accepted 13 June 2018 ticles. Therefore, it is of great scientific significance to understand the biological properties Available online 31 July 2018 of small GTPases as well as the GTPase-nano interplay, since more and more nanomedicine are supposed to be used in biomedical field. However, there is no review in this aspect. This Keywords: review summarizes the small GTPases in terms of the structure, biological function and Small GTPase its interaction with nanoparticles. We briefly introduced the various nanoparticles such as Nanoparticles gold/silver nanoparticles, SWCNT, polymeric micelles and other nano delivery systems that Ras interacted with different GTPases. These current nanoparticles exhibited different pharma- Rab cological effect modes and various target design concepts in the small GTPases study. This Rho will help to elucidate the conclusion that the therapeutic strategy targeting small GTPases might be a new research direction. It is believed that the in-depth study on the functional mechanism of GTPases can provide insights for the design and study of nanomedicines. © 2018 Shenyang Pharmaceutical University. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license. ( http://creativecommons.org/licenses/by-nc-nd/4.0/ ) and GDP in cytoplasm [2] . These small GTPases act as molecu- 1. Introduction lar switches in cells, affecting almost all cellular processes [3] . The most prominent member of small GTPase family is the Small GTPase family is a GTP-binding protein family which Ras GTPase, thus the family is also called the Ras superfamily can be commonly found in eukaryotic cells [1] . It is a kind [4,5] . of GTPases can achieve mutual transformation between GTP ∗ Corresponding author. Shenyang Pharmaceutical University, No. 103, Wenhua Road, Shenyang 110016, China. Tel.: +86-10-82802791. E-mail address: [email protected] (Q. Zhang). Peer review under responsibility of Shenyang Pharmaceutical University. https://doi.org/10.1016/j.ajps.2018.06.004 1818-0876/© 2018 Shenyang Pharmaceutical University. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license. ( http://creativecommons.org/licenses/by-nc-nd/4.0/ ) Asian Journal of Pharmaceutical Sciences 14 (2019) 30–39 31 [7,8] . The Ras subfamily protein is almost the generic compo- 2. Structure and action mechanism of small nent in signaling pathway of eukaryotes (including vertebrate, GTPases invertebrate and yeast), which plays a key role in the develop- ment, proliferation, differentiation and survival of eucaryon. 2.1. Structure of small GTPases In addition to the widely expressed major Ras isoforms, the highly conserved H-, K- and N-Ras exhibit diverse biologi- The analysis of the small GTPase protein crystal structure in- cal properties [12,13] . H-ras, K-ras and N-ras genes are located dicates that the GTP binding domain of this type of protein can on chromosomes 11, 12 and 1, respectively. K-ras gene is also be subdivided into five relatively conserved motifs G1–G5. G1 known as the p21 gene because it encodes a 21 kDa Ras pro- motif (I) is a purine nucleotide binding signal; G2 motif (E) is in tein. K-Ras has the largest impact on human cancer. one of two segments that redirects with GDP or GTP binding function and provides major component of the effector bind- 3.2. Rho subfamily ing surface; G3 motif (II) is related to the binding of nucleotide- + related Mg 2 ; G4 motif (III) brings the hydrogen bond in con- Rho GTPase family contains well-developed Rac1, RhoA and tact with the guanine ring; G5 motif ( Ⅳ ) makes indirect as- Cdc42 which modulate the formation of cytoskeleton, cell po- sociations with the guanine nucleotide [ 6 –8 ]. Taken together, larity, cell cycle progression and signal network of gene ex- these elements constitute the conserved ∼20 kDa domain and pression [14–16] . RhoA, Rac1 and Cdc42 possess the most obvi- shared by all Ras superfamily proteins. ous members [17,18] . They serve as the molecular switches in separate or correlative signaling pathways [19] . These signal- 2.2. Action mechanism of small GTPases ing pathways link the plasma receptors to activate cytoskele- ton reorganization and the subsequent biological effect. Cdc42 While participating in physiological activity, the molecular and Rho can be commonly found in yeast and most mam- structure of small GTPases present two forms which support malian cells, while Rac can only be observed in the latter [20] . mutual transformation, GTP-binding activated state and GDP- Actually, the three kinds of protein play the same signif- binding non-activated state, which can also be called as “ON” icant role in modulating cell polarity, genetic transcription, state and “OFF” state, respectively [3]. cell cycle progression, microtubule kinetics, vesicle trafficking, The hydrolysis of GTP to GDP is mediated by GTPase- extracellular matrix (ECM) remodeling and various enzymatic activated proteins (GAPs), and the exchange of GDP to GTP is activities (using NADPH oxidase activity to generate the reac- mediated by guanine nucleotide exchange factors (GEFs) [9]. tive oxygen, ROS) [21] . GEFs and GAPs coexist in most cells, increasing the diversity of signals that regulate small GTPases activity [8] . Guanine 3.3. Rab subfamily nucleotide dissociation inhibitors (GDIs) are contrary to ex- change factors. GDI specifically binds GDP-bound GTPase and Rab subfamily is the largest subfamily in Small GTPase Protein inhibits GDP release ( Fig. 1 B) [10] . family [1] . Amid the 93 Small GTPases family members of Ara- bidopsis, 57 belong to Rab subfamily. Rab subfamily modulates 3. Classification of small GTPase protein the vesicle trafficking and protein transport of eukaryocyte by regulating complex vesicle trafficking and microtubule system Ras GTP enzyme was initially found to be a mutation of GT- activities. Pase in various cancers. As time goes by, many GTP enzymes At present, there are 60 kinds of Rab proteins (including are found to have the similar 3D structure with Ras. At present, isomers) which play an important role in promoting and mod- the family has over 150 members making it a superfamily. ulating the berth and integration of trafficking vesicle ( Fig. 2 ). On the FASEB Summer Consultative Conference in 1992, the Each organelle has at least one kind of Rab protein and differ- comprehensive naming principle of Ras-like GTPase was es- ent membranes have different Rab proteins. tablished, dividing the small G protein into five subfamilies of Ras, Rho, Rab, Arf/Sar and Ran according to the sequence, 3.4. Arf subfamily structure and function. The sorting criterion is now widely ac- cepted. Recently, Rad, Rap, Rheb, Rit and Miro are also included Similar with Rab protein, the ADP-ribosylation factor (Arf) sub- into the superfamily [11] . family protein is the major regulatory factor of the biosyn- Extensive researches on each family of small GTP enzyme thesis of trafficking vesicle in cells [22] . Different from Rab family in term of cancer only focused on how these protein protein which works in single step of membrane transporta- families control the no carcinogenic process (such as immu- tion, Arf protein can work in various steps. For example, Arf nity and inflammation) at the beginning. The functions of can control (1) formation of coat protein I (COPI)-coated vesi- these GTP enzymes are greatly overlapped. Ras takes charge cle supporting antiporter between Golgi and ER; (2) formation of cell proliferation, Rho is used for cell morphology, Ran is of clathrin/adaptin 1 (AP1) compound-related vesicle in trans- used for nuclear transport, and Rab and Arf are used for vesi- Golgi network (TGN) and immature vesicle and (3) formation cle trafficking [8] . of endosome containing AP3 [6] . 3.1. Ras subfamily 3.5. Ran family Ras superfamily is the first and the most diversified subfamily. Ran is a kind of small GTPases with higher expressive abun- It plays a large role in mediating immunity and inflammation dance in eukaryocyte [23] . It can modulate the formation of 32 Asian Journal of Pharmaceutical Sciences 14 (2019) 30–39 Fig. 1 –(A) Schematic diagram of the small GTPase protein sequence. (B) Regulation of small GTPase activity. GTPases cycle between their GTP-bound active and GDP-bound inactive form. They are activated by guanine-nucleotide exchange factors (GEFs), which remove GDP, thus enabling excess cellular GTP to bind. The binding of active GTPase to downstream effector proteins elicits cell responses. GTPase-activating proteins (GAPs), which increase the GTPase activity, are the off-switch. Inactive Rac is sequestered in the cytosol by guanine-nucleotide dissociation inhibitors (GDIs). Reproduced with permission from [78] . Copyright 2018 John Wiley & Sons, Inc. cell spindle apparatus, cell cycle progression, structure and function of karyotheca, material transport of nucleoplasm, 4. Function of small GTPase and its role in cell redox reaction and RNA nuclear export, RNA synthesis nano delivery system and processing, etc.
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