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Home , HERC3, Ubiquitin ligase

Bracco E, Panuzzo C, Pergolizzi B. J Immunol Sci. (2018); 2(1): 46-49 Journal of Immunological Sciences

Mini Review Open Access

A short evolutionary journey across the HERC Enrico Bracco2*, Cristina Panuzzo1, Barbara Pergolizzi1* 1Dept. of Clinical & Biological Sciences, University of Turin, Italy 2Dept. of Oncology, University of Turin, Italy

Article Info ABSTRACT

Article Notes HECT ubiquitin ligases are key components of the eukaryotic ubiquitin- Received: December 22, 2017 system controlling different cellular physiological aspects as well Accepted: February 05, 2018 as the genesis of several human diseases. Among the HECT family, the HERC *Correspondence: subfamily members are characterized by having one or more RCC1-like domains, Dr. Enrico Bracco, Department of Oncology, University of a C-terminal HECT domain and the molecular mass ranging approximately Turin, AOU S. Luigi, 10043 Orbassano TO, Italy; from 120 kDa to 500 kDa. Due to their large size , some of them are refractory E-mail: [email protected]. to functional characterization. We have recently identified and functionally Dr. Barbara Pergolizzi, Dept. of Clinical & Biological characterized a novel large HECT member in Dictyostelium discoideum that, in Sciences, University of Turin, Italy; many aspects, exhibits structural similarities with the mammalian large HERC1. E-mail: [email protected] In the present minireview , we shortly summarize and revise the current phylogenetic history of HERC among the different living organisms. © 2018 Bracco E. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License.

Introduction Ubiquitination, which is the covalent ligation of ubiquitin to a , is associated with almost every cellular process including signal transduction, DNA damage repair, cycle regulation and autophagic clearance. The process involves three sequential steps each of which is catalysed by a different class

dependent way, by the ubiquitin activating (E1). Afterwards theof . activated In ubiquitin the first isstep physically the ubiquitin transferred is activated, to the in ubiquitin an ATP-

the ubiquitination cascade, catalysing the transfer of ubiquitin from conjugatingan E2 enzyme enzyme to form (E2). a Finally, covalent E3 ligbondases with carry a out substrate the final lysinestep in1 (Figure 1).

stimulate the ubiquitin transfer either through a direct or an indirectThree mechanism, distinct families named of E3RING lig ases(Really have Interesting been identified, New ),which

2 . HECT (Homologous to the E6AP Carboxyl Terminus) and RBR (Ring BetweenIn human Ring) beings RING is the largest family with more than 600 putative members that do not have a direct catalytic role in protein ubiquitination but basically, they act as scaffold facilitating the interaction between E2 and the substrates. In contrast to RING E3

ligases, the HECT and RBR family members catalyse the ubiquitin thentransfer covalently to the substratelinked to throughthe substrate a two-step3,4. HECT reaction: E3s can ubiquitin either is first transferred to a catalytic residue on the E3 and

Page 46 of 49 Bracco E, Panuzzo C, Pergolizzi B. J Immunol Sci. (2018); 2(1): 46-49 Journal of Immunological Sciences

of t I) a catalytic HECT domain II) one or more (up to wo conserved domains: 8. HECT is a domain of ~350 localized at their C-terminus and three) RCC1-like domain (RLD) foundamino in acids different firstly species described ranging in Human from yeast Papilloma to humans. Virus (HPV) E6-Associated Protein (E6AP). The HECT domain is

Structurally, it consists of two lobes, a larger 9N-terminal- contains(N-lobe) anda crucial a smaller catalytic C-terminal- cysteine (C-lobe) residue lobe and connected interacts by a short flexible linker essential for catalysis . The C-lobe interacts with the E2 enzymes10. Substrates recognition with ubiquitin during the transfer reaction while the N-lobe

tois mediatedtheir size byHERC domains members localized have been within catalogued the extended into Figure 1- Schematic representation of the ubiquitin system region N-terminal to the catalytic HECT domain.11 According, but this Ubiquitination proceeds through an initiation step during which the ubiquitin is activated by an E1 enzyme. Then, the activated small (HERC3-6) and large HERC (HERC1-2) ubiquitin is transferred to E2. Selectivity of substrate comes from evolutional considerations. classification is purely operational and not based on the E3 ubiquitin ligases, which couple with E2 to bind substrates The elaboration of a phylogenetic tree with the and catalyse the transfer of the activated ubiquitin from the E2 itself to the substrate. E3 HECT, RING and RBR domains, act sequences of all published animal HECTs from different through different reaction mechanisms. While the E3-HECT ligase catalyses by itself the ubiquitin transfer to the substrate by forming 12. Indeed, the an E3-ubiquitin intermediate, E3-RING ligase domain speciesphylogenetic suggested analysis that established the aforementioned that the small classification and large does not possess direct catalytic activity but rely on the enzymatic was,HERC subfamilies to some are extent, only distantly oversimplified related. In addition, the activity of E2 to ubiquitinate the substrates. Eventually, RBR ligases study allowed to trace the oldest common ancestral HERC combine features of both RING- and HECT-type ligases. Monosiga brevicollis function on their own or in conjunction with accessory whose genome encodes for a small HERC, mostly like the encoding gene in the choanoflagellate or adaptor protein5 mammalian HERC4 and HERC3, but not for canonical large for the substrate recognition for RING E3 ligase is mainly HERC. Animal large HERC members, namely HERC1 and accomplished by . the While requirement the selectivity of andmultisubunit specificity HERC1 is structurally characterized by a HECT domain HERC2, are giant proteins with molecular mass ≥500 kDa. region is most likely the sole that serves as the substrate recognitioncomplexes, for domain. the HECT and RBR members the N-terminal localized at its C-terminus and by a single SPRY (spl A andmore Ryanodinecomposite Receptor),than that of WD40 HERC1 (G because protein itβ-subunit contains substrate proteins of individual HECT, the physiological like repeats) and two RLDs. The architecture of HERC2 is relevanceDespite ofthe manyefforts madeof these in the interactions identification remain of potential still multiple conserved regions other than the HECT and RLD characterization of HECT E3 members is however available domains, including a Cytb5 (cytochrome b5-like) region, a unclear. Besides the animal kingdom, where the functional only for a handful of them, the evolutionary history of the DOC (DOC1/APC10), a mind-bomb/HERC2 (MIB), a Cullin7 HECT E3s and their biological roles remain still mostly proteinRecently, homology in a (CPH)genetic and suppressor a ZZ-type screeningzinc finger usingdomain. as unknown. In this respect we have recently characterized parental strain a Dictyostelium discoideum a novel large HECT member which might be a functional, mutant13 but not structural, distant relative of the large HERC E3 TORC2 deficient 6,7. In the present minireview, we will attempt to communications we identified, and signal and transduction. functionally characterized,As a matter shortly summarize and revise the long evolutionary history a giant HECT protein regulating some aspects of cell- sub-familyof the HERC E3 ubiquitin ligases members. of fact, this giant E3-ubiquitin ligase6. The controls protein G-protein displays HERC family members structural features and themediated highest cell-to-cell homology signaling to the andhuman acts large as a suppressor HERC1 (57% for domain composition throughout the evolution the TORC2-dependent PKB activity The structurally related HERC E3 ubiquitin ligases the Dictyostelium and the human protein possess a single belong to a subfamily of the HECT E3 family. The HERC similarity and 38% identity within the HECT domain). Both members are proteins of different size (ranging from of several proteins and peculiar of HERC1. Furthermore, theSPRY comparison domain, likely of themediating Dictyostelium protein interaction, typicalitin

100-120 kDa to >500 kDa), characterized by the presence giant E3-ubiqu Page 47 of 49 Bracco E, Panuzzo C, Pergolizzi B. J Immunol Sci. (2018); 2(1): 46-49 Journal of Immunological Sciences

a kingdom different from that of an animal as hitherto believed12. Indeed, the vast majority of protists organisms ligase with the human HERC1, shows that the first lacks harbour encoding for both putative small and large the RLD whose molecular function in HERC proteins is still HERC. Interestingly, the structural domain composition of andnot fullyguanine understood. releasing Indeed,factor (GRF) RLD1 for domain ARF1, andof the as GEFhuman for HERC1 may act either as a guanine exchange14. On thefactor contrary, (GEF) putative large HERC evokes that of canonical mammalian this biochemical feature is not shared with the structurally the N-terminal region of the vast majority of the protists some Rab family GTPases (Rab3a, Rab5) 15. Additionally, it HERC1 because they possess at least a RLD, SPRY,16. Animalsa single related RLD domain of the small HERCs suchHECT asand the in someurochordate cases, an ( CionaUBA domain intestinalis but all) andof them the has been reported that the RLD1 GRF activity requires the cnydarialack a WD40 (Hydra motif vulgaris) hence harbour named “HERC-like”HERC1 proteins that, binds,presence phospholipids of phosphatidylinositol-4,5-bisphosphate14. Remarkably, besides the [PI(4,5) HECT structurally, are already very close to those of mammals, P2] indicating that the RLD1Dictyostelium recognizes, giant and HECT non-covalently harbours two archetypal of the mammalian HERC1. Noteworthy, paradigmaticand SPRY domain, phospholipids the recognition motif. To our albeit characterized by a single RLD instead of the canonical a Plekstrin Homology (PH) domain that represents the theirsome size protists range suchbetween as amoebozoa,120 to 200 kDa, dinoflagellates but, besides andthe knowledge it was the first large HECT E3- apicomplexa encode for small HERC-like proteins, that is otherpossessing members a PH of the domain. amoebozoa Thus, group the protein(e.g. Dictyostelium has been domain displaying homology either with the / sp.,named Acytostelium, HectPH1. Polysphondillium This unique feature, and Tieghemostelium shared with the) canonical RLD and Hect, they possess a third additional places the Dictyostelium respectively. canonical large HERC but potentially, functionally closer kinase, tetratricopeptide or cytochrome-C motif, Remarkably, canonical small HERC encoding genes are than foreseen. Currently, HectPH1 whether structurally the structurally distant related from found also in some red and brown algae (e.g. Fistulifera HERC proteins, as such, have evolutionary emerged rather solaris, Galdieria sulphuraria and Cyanidioschyzon merolae) late, or not, remains a debated issue. Here, we attempt as well as in green plants. ubiquitin ligase going back to lower eukaryotes (protists), The latter organisms uniquely encode for canonical plantsto shortly and reviewprimitive the algae evolutionary (red and brown). history As of below HERC will E3- small HERCs and their presence is restricted to the green algae and herbaceous plants, though the latter organisms annotated genomes highlights that the phylogenetic history uniquely encode for canonical small HERC members. be briefly discussed, a database revision of the current It appears clear that the current HERCs phylogenetic of HERCIndeed, proteins thanks needs to the to accessibilitybe up-dated andto more slightly sequenced revised. and annotated genomes the scenario rapidly changed and structurally related HERC encoding genes have been animalhistory kingdom needs to but be re-assessed.evolutionary Actually, they emerged we are earlier, aware 16, as it is anthat occurrence HERC proteins that is are witnessed not exclusively by their restricted appearance to the in summarized in Table 1. protist and plant kingdoms. The molecular mechanisms identified either in the protist and plant kingdoms controlling the HERC ubiquitin ligases, as well as their Such evidence indicates that the most primitive ligase date back to open questions and answering to them will represent enzymatic regulation and substrate specificity, are so far Tableprototype 1-HERC of proteins the HERC distribution E3-ubiquitin among the protist, plant and the major future challenge to fully understand their animal kingdoms. The yellow star in the non-canonical HERC group functional roles. In this regard, the large HERCs possess indicates any single, or multiple (in various order and number), a variety of motifs whose function remains currently domain/s in addition to the RLD, SPRY and HECT that are shared with the canonical HERCs. highly conserved throughout the evolution suggesting a

Classification Canonical Non canonical mysterious. Besides the RLD domain, the SPRY motif is Small Large Small Large

RLD SPRY WD40 RLD HECT HECT RLD HECT RLD SPRY HECT substratestrictly maintained recognition, role. toCurrently, the enzymatic whether theregulation N-terminal or RLD CUL7 RLD RLD HECT APC10 domain of large HERC contribute to the specificity of the presence of HERC encoding genes in simple, and genetically amenable,both and to organisms a what extent (e.g., to amoebozoa) date remains potentially unknown. make The them very valuable and attractive models, alternative to animals, to better understand and clarify the functional roles, substrates, physical/genetic interactors and cellular substrates of these peculiar group of E3 ubiquitin ligases.

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References 9. 1. V erdecia MA, Joazeiro CA, Wells NJ, et al. Conformational flexibility underlies ubiquitin ligation mediated by the WWP1 HECT domain E3 Buetow L, Huang DT. Structural insights into the catalysis and 10. ligase. Mol Cell. 2003; 11: 249-59. regulation of E3 ubiquitin ligases. Nat Rev Mol Cell Biol 2016Oct; 2. 17(10): 626:42. Huang L, Kinnucan E, Wang G, et al. Structure of an E6AP-UbcH7 complex: insights into ubiquitination by the E2-E3 enzyme cascade. Metzger MB, Hristova VA, Weissman AM. HECT and RING finger 11. Science. 1999; Nov 12(286(5443)): 1321:6. families of E3 ubiquitin ligases at a glance. J Cell Sci. 2012 Feb 1; 125: 3. 531-7. Hochr ainer K, Mayer H, Baranyi U, et al. The human HERC family of ubiquitin ligases: novel members, genomic organization, expression W enzel DM, Klevit RE. Following Ariadne’s thread: a new perspective profiling, and evolutionary aspects. Genomics. 2005 Feb; 85(2): 4. on RBR ubiquitin ligases. BMC Biol. 2012; 10(24). 12. 153:64. Huibregtse JM, Scheffner M, Beaudenon S, et al. A family of proteins Marín I. Animal HECT ubiquitin ligases: evolution and functional structurally and functionally related to the E6-AP ubiquitin-protein 13. implications. BMC Evol Biol. 2010 Feb 22;10: 56. 5. ligase. Proc Natl Acad Sci USA. 1995; 92: 2563–7. inhibition of development in Dictyostelium due to a point mutation in P ergolizzi B, Peracino B, Silverman J, et al. Temperature-sensitive 38. Gatti M, Pinato S, Maiolica A, et al. RNF168 promotes noncanonical K27 ubiquitination to signal DNA damage. Cell Rep. 2015; 10(2): 226- 14. the piaA gene. Dev Biol. 2002; 251: 18-26. 6. Gar cia-Gonzalo FR, Bartrons R, Ventura F, et al. Requirement of P ergolizzi B, Bracco E, Bozzaro S. A new HECT ubiquitin ligase phosphatidylinositol-4,5-bisphosphate for HERC1-mediated guanine regulating chemotaxis and development in Dictyostelium discoideum. nucleotide release from ARF proteins. FEBS Lett. 2005Jan 17; 7. J Cell Sci. 2017; 1;130(3): 551:62. 15. (17;579(2)): 342:8. P ergolizzi B, Bozzaro S, Bracco E, and G-PDST, E2180. UiDIJMSOp, R otin D, Kumar S. Physiological functions of the HECT family of PMCID: diRPPPC, et al. G-Protein Dependent Signal Transduction and 16. ubiquitin ligases. Nat Rev Mol Cell Biol. 2009; 10(6): 398-409. 8. Ubiquitination in Dictyostelium. Int J Mol Sci. 2017; Oct 19: 18(0). Gr au-Bové X, Sebé-Pedrós A, Ruiz-Trillo I. A genomic survey of HECT Sánchez-Tena S, Cubillos-Rojas M, Schneider T, et al. Functional and ubiquitin ligases in eukaryotes reveals independent expansions of pathological relevance of HERC family proteins: a decade later. Cell the HECT system in several lineages. Genome Biol Evol. 2013; 5(5): Mol Life Sci. 2016; 73(10): 1955-68. 833-47.

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