Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

RBR E3 Ubiquitin Ligases

Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_101592


Human RBR E3 Ubiquitin Ligase Family Members

ANKIB1 (KIAA0708/KIAA1386), ARA54 (TRIAD2/RNF14/HFB30/HRIHFB2038), Dorfin (IBRDC3/RNF19), HHARI (Ariadne-1/H7-AP2/MOP-2/ARIH1), HOIL-1 (RBCK1/C20orf18/RNF54/XAP3/XAP4), HOIP (PAUL/RNF31/ZIBRA), Parc (Cullin-9/CUL-9, H7AP1), Parkin (Prkn/Park2), RNF144A (KIAA0161)/UBCE7IP4), RNF144B (p53RFP/PIR2/IBRDC2), RNF19B (IBRDC3/NKLAM), RNF217 (C6orf172/IBRDC1), TRIAD1 (Ariadne-2), TRIAD3 (RNF216/ZIN).

Historical Background

The RBR E3 ligase family, comprised of two conserved zinc-binding RING-like domains surrounding a novel zinc-binding motif, was originally identified independently by two research groups. This newly recognized zinc-binding motif was named DRIL (double RING finger linked), as it was exclusively found between two conserved RING-like sequences, and the supradomain was named TRIAD (two RING fingers and a DRIL) (van der Reijden et al. 1999). Likewise, the conserved motif was also recognized by a group studying Parkin who called the central domain between the conserved RING-like domains an IBR domain (in-between-ring) (Morett and Bork 1999). Three years later, the RBR nomenclature (RING1-betweenRING-RING2) was canonized after an extensive phylogenetic analysis using a more permissive definition of this motif found only in eukaryotes. It was also hypothesized that members of this newly defined family may all possess E3 ubiquitin ligase activity (Marin and Ferrus 2002), which has since been confirmed by numerous research groups from many biological fields of study. The molecular basis for how the RBR E3 ligases are activated, bind and recognize their substrates, and specifically link ubiquitin to their targets is presently being elucidated through clever biochemistry experiments in combination with molecular, cell, and structural biology approaches. The 14 human RBR family members including all published structures and proteins experimentally observed to interact with RBR E3 ligases are summarized in Table 1.
RBR E3 Ubiquitin Ligases, Table 1

Structures & Experimentally Identified Interactors

NAME (Uniprot)

Alternate names

PDB ID (domain, method)

Identified interacting protein





ARA54 (Q9UBS8)






UbcH6 (UBE2E1)

UbcH8 (UBE2L6)

UbcH9 (UBE2E3)

Androgen receptor

Heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1)

p300/CBP-associated factor

T-cell factors 1 and 4 (TCF1, TCF4)

Dorfin (Q9NV58)




UbcH7 (UBE2L3)

UbcH8 (UBE2L6)

α-synuclein interacting protein (Synphillin-1, Sph1)

Calcium-sensing receptor

Cu/Zn SOD1 (ALS mutants; G37R/H46R/G85R/G93A)

Ubiquitinated substrates (not defined)

Valosin-containing protein (p97/Cdc48 homologue)







2M9Y (Rcat, NMR)

4KBL (Full, X-ray)

4KC9 (Full, X-ray)

UbcH7 (UBE2L3)

UbcH8 (UBE2L6)


α-synuclein interacting protein (Synphilin-1, Sph1)

Cullin-1,2,3,4A (NEDD8-dependent)

Transcription factor single-minded (SIM2)

Translation initiation factor 4F homologous protein (4EHP)








4DBG (UbLD, X-ray)

3BOA (NZF, X-ray)

3BO8 (NZF, X-ray)

2CRC (zf-RanBP, NMR)

Cellular inhibitor of apoptosis proteins 2/3 (cIAP1/2)

HOIL-1 interacting protein (HOIP)

Nucleotide-binding oligomerization domain protein 2 (NOD2)

Polyubiquitin chains (linear>K63)

Protein kinase C (PKC)

Retinoic acid-inducible gene 1 protein (RIG-1)

Shank-associated RH domain-interact. protein (Sharpin, Sipl1)

suppressor of cytokine signaling 6 (SOCS-6)

Tumor necrosis factor α-induced protein 3 (A20)

Tumor necrosis factor receptor Type1 DEATH domain (TRADD)

Tripartite motif-containing protein 25 (TRIM25)

Tumor receptor-associated factor 2 (TRAF2)





2CT7 (BRcat, NMR)

4DBG (UBA, X-ray)

4JUY (PUB, X-ray)

4LJQ (Rcat-LDD, X-ray)

4P09 (Rcat-LDD, X-ray)

5EDV (RBR+E2/Ub, X-ray)

5LJN (PUB, X-ray)

UbcH7 (UBE2L3)

UbcH5A (UBE2D1)

UbcH5B (UBE2D2)

UbcH5C (UBE2D3)

E2-25K (UBE2K)

Shank-associated RH domain-interacting protein (Sharpin, Sipl1)

B-cell surface antigen CD40 (CD40)

Heme-oxidized IRP2 ubiquitin ligase-1 (HOIL-1)

Muscle-specific receptor tyrosine kinase (MuSK)

NF-κB essential modulator (NEMO)

Nucleotide-binding oligomerization domain protein 2 (NOD2)

OTU domain deubiquitinase with linear linkage specificity (Gumby)

Polyubiquitin chains (K63>linear>K48)

Tripartite motif-containing protein 25 (TRIM25)

Tumor necrosis factor α-induced protein 3 (A20)

Tumor necrosis factor receptor 1 signal. comp. (TNF-RSC)

Parc (Q8IWT3)





UbcH7 (UBE2L3)




Ring box protein-1 (Rbx1)

Parkin (O60260)




1MG8 (UbLD, NMR)

2JMO (BRcat, NMR)

2ZEQ (UbLD, X-ray)


3B1L (UbLDR33Q, X-ray)

2M48 (BRcat-Rcat, NMR)

4K7D (RRBR, X-ray)

4K95 (Full, X-ray)

2LWR (Rcat, NMR)

4BM9 (RRBR, X-ray)

4I1F (RRBR S223P, X-ray)

4I1H (RRBR, X-ray)

5C9V (RRBR G319A, X-ray)

5CAW (Full, X-ray)

5C1Z (Full Δ84-143, X-ray)

5C23 (Full S65D, X-ray)

4ZYN (Full Δ86-130, X-ray)

Ubc7 (UBE2G1)

UbcH7 (UBE2L3)

UbcH5c (UBE2D3)

UbcH6 (UBE2E1)

UbcH8 (UBE2L6)

UbcH13 (UBE2N)

Ubiquitin-conjugating enzyme variant 1a (Uev1a)


20S proteasome subunit α4 (PSMA7/XAPC7, Subunit α type7)

26S proteasome non-ATPase reg. subunit4 (Rpn10/S5a)

α-synuclein interacting protein (Synphylin-1, Sph1)

Acute lymphoblast. Leukemia-1 fusPart. chromo6 (Afadin/AF-6)

Aminoacyl tRNA synthase complex coactiv. (p38/JTV-1/AIMP2)

Apoptosis regulator Bcl-2

Bcl-2-associated athanogene 5 (BAG5)

Calcium-/calmodulin-dependent serine kinase (CASK/Lin2)

Carboxy terminus of Hsp70-interacting protein (CHIP)

Casein kinase 1 (CK1)

Catenin beta-1 (β-catenin)

Chondroitin-polymerizing factor (ChPF/Klokin1)

Cullin-1 (CUL-1)

Cyclin-dependent kinase 5 (Cdk5)

Cyclin E

DJ-1 peptidase

Dopamine transporter (DAT)

E3 SUMO-protein ligase Ran binding protein 2 (RanBP2)

Epidermal growth factor receptor substrate 15 (Eps15)

F-box/WD repeat-containing protein 7 (FBX30/SEL-10)

Heat shock 70 kDa protein (Hsp70/chaperone protein DnaK)

Histone deacetylase 6 (HDAC6)

Leu-rich PPR motif-containing protein (LRPPRC, LRP130)

Leu-rich repeat kinase 2 (LRRK2)

LIM kinase-1 (LIMK1)

Machado-Joseph disease protein 1 (Ataxin-3)

Mitochondrial Rho GTPase (Miro)

Mitofusin-1 (MFN1)

Mitofusin-2 (MFN2)

Mortalin (HSPA9, GRP75, PBP74)

Neuronal DnaJ/Hsp40 chaperone HSJ1a (DNAJB2a)

O-glycosylated α-synuclein (αSp22)

Parkin-associated endothelin receptor (Pael-R)

Parkin coregulated gene protein (PACRG/Glup)

Parkin-interacting substrate (PARIS/ZNF476)

Prolierating cell nuclear antigen (PCNA)

Protein interacting with C kinase 1 (PICK1/PRKCA BP)

Protein kinase A (PKA)

Protein kinase C (PKC)

PTEN-induced putative kinase 1 (PINK1)

Ring finger protein 41 (RNF41/NRDP1/FLRF)

Septin4 (ARTS/CDCrel-2)

Septin5 (CDCrel-1/PNUTL1)

Small ubiquitin-related modifer-1 (SUMO-1)

Synaptotagmin XI (Syt11)

Tar-DNA binding protein-43 (TDP-43)

Transcription factor single-minded 2 (SIM2)

Translocase outer mitochonMemb 70 homologA (TOMM70A)

Tubulin (α, β, and γ)

Tyrosine protein kinase ABL1 (c-Abl)

RNF144A (P50876)




UbcH7 (UBE2L3)

RNF144B (Q7Z419)





UbcH7 (UBE2L3)

UbcH8 (UBE2L6)

Bcl-2 associated protein X (BAX)

CDK-interacting protein 1 (p21WAF1)

Leukemic nucleophosmin protein (NPMc)








RNF217 (Q8TC41)




TRIAD1 (O95376)




UbcH7 (UBE2L3)

UbcH8 (UBE2L6)

UbcH6 (UBE2E1)

UbcH13 (UBE2N)

Cullin-5 (NEDD8-dependent)

Growth factor independence 1 (Gfi1)

Growth factor independence 1B (Gfi1B)

Mouse double minute 2 homolog E3 ligase (MDM2)

Nuclear inhibitor of κB β (IκBβ)


Promyelocytic leukemia–retinoic acid receptor α (PML–RARα)





UbcH7 (UBE2L3)

UbcH8 (UBE2L6)

Killer cell Ig-like receptor (KIR) 2DL4

Receptor interacting serine/threonine-protein kinase-1 (RIP1)

TNF receptor-associated factor 3 (TRAF3)

Toll/interleukin-1 receptor adaptor protein (TIRAP)

Toll-like receptors 3,4,5, and 9 (TLR3, TLR4, TLR5, TLR9)

Virion infectivity factor (Vif) of HIV-1

Abbreviations: BRcat Benign-catalytic, CPH Cul7/Parc/Herc2 domain, Full Full-length, LDD Linear ubiquitin chain determining domain, NMR nuclear magnetic resonance spectroscopy, NZF Npl4 zinc finger, PUB Peptide:N-glycanase/UBA or UBX-containing proteins, Rcat Required for catalysis, RBR RING1-IBR-RING2, RRBR RING0-RING1-IBR-RING2, UBA ubiquitin-associated, UbLD ubiquitin-like domain, X-ray X-ray crystallography, ZF zinc finger

Websites: UNIPROT – www.uniprot.org, PDB - http://www.rcsb.org/pdb/home/home.do

The RBRs are E3 ubiquitin ligases involved in the ubiquitylation signaling pathway. Ubiquitylation is a posttranslational protein modification that regulates numerous intracellular functions in eukaryotes. These roles include modulating protein-protein and/or protein-DNA interactions, regulating transcription, cell-cycle progression, intercellular signaling, subcellular localization, and 26S proteosomal-mediated degradation of polyubiquitylated substrates (Komander and Rape 2012). Target ubiquitylation occurs through a three-step sequential transfer of ubiquitin onto an ubiquitin activating enzyme (E1), then onto an ubiquitin conjugating enzyme (E2), then in conjunction with an ubiquitin ligase (E3) onto the substrate (Fig. 1a).
RBR E3 Ubiquitin Ligases, Fig. 1

(a) The ubiquitylation pathway involving an RBR E3 ligase. Ubiquitin (yellow) is first activated by an ubiquitin activating enzyme (E1, cyan) through the hydrolysis of ATP to form a thioester between the C-terminus of ubiquitin and the catalytic cysteine of the E1. Next, the ubiquitin is transferred to the catalytic cysteine of an ubiquitin conjugating enzyme (E2, green) through a transthiolation reaction. The E2~ubiquitin conjugate then engages with an RBR E3 ligase via the RING1 domain (grey; BRcat in orange; Rcat in purple). The conserved catalytic cysteine found in the Rcat domain performs a transthiolation reaction, analogous to a HECT E3 ubiquitin ligase, which then reacts with a lysine side chain on a substrate protein to form an isopeptide bond between the ε-NH2 of lysine and the C-terminus of ubiquitin. (b) Structural representations of RBR domains – RING1 from Parkin (PDB 5C1Z), BRcat from Parkin (PDB 2JMO), and Rcat from HHARI (PDB 2MY9). Residues involved in Zn2+ coordination are shown in yellow. The conserved catalytic cysteine found in the Rcat is highlighted with a red star. (c) Structure of HOIP RBR in complex with UbcH5B~ubiquitin conjugate (PDB 5EDV). In this first reported structure of an RBR E3 ubiquitin ligase in its “active” conformation, the catalytic cysteine in the RING2L of HOIP from chain A (analogous to Rcat in other RBR E3 ubiquitin ligases) is brought into close proximity of the isopeptide linked C-terminus of ubiquitin in the UbcH5B~ubiquitin complex by the RING1 domain of HOIP from chain B (highlighted with a red star). In this bipartite configuration, the catalytic cysteine is poised to accept the ubiquitin from the UbcH5B~ubiquitin conjugate through a transthiolation reaction

Expanding upon a previous review focusing on the structural aspects of the RBR E3 ligases (Spratt et al. 2014), this encyclopedia entry concisely summarizes important historical findings on the RBR E3 ligases, their expression and intracellular localization, their relevance to various human diseases, and some recent structural advances in the RBR E3 ligase field.

RBR E3 Ubiquitin Ligase Expression and Intracellular Localization

Most RBR E3 ligases are widely expressed in all tissues. Several RBR E3 ligases are highly expressed in the brain, such as Parkin, Dorfin, and Parc, suggesting a role for these E3 ligases in neuronal protection. For example, Parkin is shown to associate with a Skp1/Cullin/F-box-like ubiquitin ligase complex to protect postmitotic neurons from apoptosis triggered by excessive cyclin activity. Parc has a role in protecting neuron cells from apoptosis in response to mitochondrial damage through mediating the ubiquitylation and degradation of cytochrome c, a signal for apoptosis. Likewise, Dorfin is ubiquitously expressed in neurons. Most of the RBR E3 ligases are cytosolic (i.e., Parc, Parkin, HHARI, Dorfin, HOIP, ARA54, ANKIB1, and HOIL-1). However, some RBR E3 ligases localize to the cell membrane. For example, both RNF144A and RNF144B have unique transmembrane domains located near their C-termini that are proposed to have dual roles of (i) maintaining their membrane localization and (ii) regulating their ubiquitin E3 ligase activity. RNF144A plays a key role in mediating DNA repair by regulating the expression levels of cytoplasmic DNA-dependent protein kinases (DNA-PKs) during nonhomologous end-joining DNA repair (Ho et al. 2014). RNF144A also promotes the ubiquitylation and proteasomal degradation of DNA-PKs to enhance cell apoptosis during persistent or severe DNA damage insults.

Translocation within the cell is required for some of the RBR E3 ligases to perform their specific function. For example, Parkin is translocated to the mitochondrial membrane in the presence of PTEN-induced kinase (PINK1) in response to mitochondria depolarization (Vives-Bauza et al. 2010). Likewise, the transmembrane domain of RNF144B is suggested to be important in the translocation of RNF144B to mitochondria in response to the activation of the proapoptotic protein Bax (Benard et al. 2010).

RBR E3 Ubiquitin Ligases and Disease

Dysfunction of RBR E3 ligases through misfolding and/or improper enzyme regulation has been associated with various diseases including cancer development, disorders of the immune system, and neurodegenerative diseases. For example, Parkin, Dorfin, and HHARI have been implicated in various neurodegenerative diseases including autosomal recessive juvenile Parkinsonism (AR-JP), Parkinson’s disease (PD), and amyotrophic lateral sclerosis (ALS). Loss-of-function mutations in Parkin have been suggested to be the causative agent in AR-JP and PD. Parkin attaches ubiquitin to synaptic proteins including synphilin-1 and α-synuclein, both of which are major protein components of Lewy bodies (LB) found in patients with PD (Beyer et al. 2008). Dorfin is involved in PD by mediating the ubiquitylation of synphilin-1 and is found to colocalize with LB. Furthermore, Dorfin has been suggested to play a role in ALS due to (i) Dorfin predominantly colocalizing in LB-like inclusions discovered in sporadic and familial ALS, and (ii) Dorfin specifically ubiquitylating mutant superoxide dismutase-1 (SOD1), rather than wild-type SOD1 (Niwa et al. 2002). HHARI is found to be one of the protein components of human LB and is able to induce aggresome formation in mammalian cells, suggesting a role for HHARI in neurodegenerative diseases.

Linear ubiquitin chains are assembled by the linear ubiquitin assembly complex (LUBAC), which is comprised of the RBR E3 ligases HOIP and HOIL-1 as well as Sharpin. Studies have shown that the LUBAC is essential for the activation of NF-kB pathway that mediates the immune and inflammatory response to bacterial and viral infections. Dysfunction of either HOIP or HOIL-1, members of the LUBAC, has been implicated in disorders of the immune system including immunodeficiency and auto-inflammation (Boisson et al. 2015). For example, loss-of-function mutations in HOIL-1 compromise linear ubiquitin chain synthesis leading to abnormal activities of members of the NF-kB signaling pathway, which in turn cause defects in the immune system. Furthermore, mutational and cellular immunoprecipitation studies show that HOIP is negatively mediated by ubiquitylation stimulated by Toll-like receptor 4 (TLR4), which in turn downregulates the NF-kB pathway. Taken together, the RBR E3 ligases HOIP and HOIL-1 are important components of the LUBAC complex and play significant roles in maintaining the homeostasis of the immune response either by activation or suppressing the NF-kB signaling pathway.

Several RBR E3 ligases are suggested to play roles in cancer, specifically through the regulation of the oncogenic transcription factor p53. Mutations in p53 have been attributed to 50% of cancers discovered to date. For example, TRIAD1 has been shown to regulate p53-dependent apoptosis through its activation of p53 and inhibition of MDM2-mediated p53 degradation. Similarly, Parc strongly associates with the C-terminus of p53 to mediate the subcellular location of p53 as well as mediates cellular apoptosis by regulating the ubiquitylation and degradation of BIRC5, an inhibitor of apoptosis protein. RNF144B is involved in regulation of apoptosis by modulating the cellular levels of Bax (Benard et al. 2010).

The RBR E3 ligases are tightly regulated to ensure their proper function. For example, Parkin is activated by PINK1-dependent phosphorylation of ubiquitin (Koyano et al. 2014). While in most cases posttranslational modifications can enhance the activity of Parkin E3 ligase activity (i.e., phosphorylation and neddylation), some modifications of Parkin can lead to loss of function (i.e., ubiquitylation, oxidation, and S-nitrosylation) (Walden and Martinez-Torres 2012). Furthermore, protein-protein interactions between Parkin and SUMO, Eps15, or endophilin-1A have been shown to increase the activity of Parkin, while Myc-14-3-3η inactivates Parkin. The transcription, expression, and subcellular localization of Parkin are tightly regulated.

Structure and Function of RBR E3 Ubiquitin Ligases

In recent years, a number of structures of the RBR domains and of full-length RBR proteins have been solved, each further expanding our understanding of the underlying mechanism (Table 1). The RBR E3 ubiquitin ligases possess a conserved sequence of three double-zinc binding motifs. Prior to 2011, the RBR E3 ligases were thought to use an unknown tandem RING mechanism thought to be similar to the RING E3 ligase subfamily. However, in 2011 a seminal paper from Dr. Rachel Klevit’s laboratory (University of Washington) clearly demonstrated that the RBR E3 ligases were in fact a unique E3 ligase family that employs a RING/HECT hybrid mechanism, whereby the RING1 acts as a scaffold for the E2~ubiquitin conjugate that can properly transfer the ubiquitin cargo to a required conserved cysteine found in the RING2 domain during ubiquitylation (Wenzel et al. 2011). In 2013, numerous structures were published, almost simultaneously, showing the structure of the RING2 domain of Parkin (PDB 4I1F, 4BM9, 4K7D, 4K95, 2LWR, 2M48), HHARI (PDB 4KBL, 4KC9, 2M9Y), and HOIP (PDB 4LJO, 4LJP, 4LJQ). These structures revealed that the RING2 domain adopts a fold similar to the IBR by coordinating two zinc ions in a linear fashion with the conserved active cysteine located in a loop lying between the first two pairs of zinc-binding residues. Consequently, the RING2 and IBR have been renamed Rcat (required for catalysis) and BRcat (benign-catalytic), respectively, to more accurately reflect their structure and function (Spratt et al. 2014) (Fig. 1b, c).

All of the full length and partially truncated RBR structures that have been solved to date for Parkin and HHARI have shown that these RBRs are tightly regulated through autoinhibition. For example, the N-terminal UblD maintains Parkin in an inactive state (Chaugule et al. 2011) that is relieved by the phosphorylation of UblD and/or ubiquitin by PINK1 to reveal the ubiquitin-binding site of the E2~ubiquitin conjugate on RING1 (Kumar et al. 2015). Likewise, the unique RING0 domain of Parkin occludes the catalytic cysteine of Rcat blocking it so that it is unable to accept or donate ubiquitin. Autoinhibition of HHARI occurs in a similar fashion, whereby the Ariadne domain C-terminal to the RBR domain blocks the catalytic cysteine of Rcat (Duda et al. 2013) which is relieved upon interacting with neddylated Cullin RING E3 complexes to expose the Rcat catalytic cysteine (Scott et al. 2016). Furthermore, the autoinhibition of HOIP ubiquitylation by its UBA domain can be counteracted by the binding of the HOIL-1 UblD (Stieglitz et al. 2012).

The unique domains of the RBR family members mediate protein-protein interactions and control the mode of ubiquitylation (mono versus poly-Ub, linkage specificity). For example, Parkin predominately polyubiquitylates substrates with K48 linkage specificity to target its substrates for degradation by the 26S proteasome. In contrast, HHARI’s association with neddylated Cullin RING E3 complexes promotes substrate monoubiquitylation (Scott et al. 2016). Finally, HOIP in an active LUBAC complex catalyzes the formation of linear ubiquitin chains directed by the Rcat in tandem with the linear ubiquitin chain determining domain (LDD) of HOIP (aka RING2L).


The RBR E3 ligases are important enzymes involved in all aspects of cellular activities. Over the past 15 years, the research community has rapidly been expanding our knowledge on the intracellular localization of each RBR E3 ligase and the biological functions that each of these fascinating enzymes regulate. There is a myriad of new structural data on the RBR E3 ligases available including the recent active conformation of HOIP RBR in complex with an UbcH5B-ubiquitin conjugate revealing how ubiquitin can be brought into close proximity of the catalytic cysteine of RING2 using a bipartite mechanism (Lechtenberg et al. 2016) (Fig. 1c). Future studies focusing on elucidating the binding partners of RBR E3 ligases and the mechanisms underlying their recognition and sites of modification will provide valuable insights into future therapeutic strategies for RBR-relevant diseases.


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Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  • Steven A. Beasley
    • 1
  • Yaya Wang
    • 1
  • Donald E. Spratt
    • 1
  1. 1.Gustaf H. Carlson School of Chemistry and BiochemistryClark UniversityWorcesterUSA