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PubMed1993

Sites of RNA polymerase III transcription initiation and Ty3 integration at the U6 gene are positioned by the TATA box.

The function of a TATA element in RNA polymerase (EC 2.7.7.6) III transcription of a naturally TATA-containing U6 snRNA gene and a naturally TATA-less tRNA gene was probed by transcription and Ty3 transposition analyses. Deletion of the TATA box from a U6 minigene did not abolish transcription and Ty3 integration but changed the positions of initiation and insertion. Insertion of the U6 TATA box at three positions upstream of the TATA-less SUP2 tRNA(Tyr) gene resulted in novel transcription initiation and Ty3 integration patterns that depended upon position of the insertion. Nevertheless, the predominant tRNA gene initiation sites were not affected by insertion of the TATA sequence and remained at a fixed distance from the internal box A promoter element. Insertions of the TATA box upstream of a SUP2 box A mutant affected the level of transcription and restricted the use of upstream start sites, but they neither enhanced the use of TATA-dependent initiation sites nor restored expression to the level of the wild-type gene. We conclude that (i) the U6 TATA box is essential in vivo for correct initiation but not for transcription, (ii) a TATA box does not compensate for a weak box A sequence and so cannot perform equivalently, and (iii) the TATA-binding protein, and probably components of transcription factor IIIB, are present on the target at the time of Ty3 integration.

Base Sequence↗

PubMed2001

Interactions between HMG boxes.

Many proteins consist of subdomains that can fold and function independently. We investigate here the interaction between the two high mobility group (HMG) box subdomains of the nuclear protein rHMG1. An HMG box is a conserved amino acid sequence of approximately 80 amino acids rich in basic, aromatic and proline side chains that is active in binding DNA in a sequence or structure-specific manner. In the case of HMG1, each box can bind structural DNA substrates including four-way junctions (4WJs) and branched or kinked DNA duplexes. Since proteins containing up to six HMG boxes are known, the question arises whether linking subdomains together influences the folding or function of individual boxes. In an effort to understand interactions between individual DNA-binding domains in HMG1, we created new fusion proteins: one is an inversion of the order of the AB di-domain in HMG1 (BA); in the second, we added a third A domain C-terminal to the AB di-domain (ABA). Pairs of boxes, AB or BA, behave similarly and are functionally active. By contrast, the ABA triple subdomain construct is partially unfolded and is less active than individual boxes or di-domains. Thus, long-range inter-domain effects can influence the activity of HMG boxes.

Amino Acid Sequence↗

PubMed1997

Energy expenditure of a noncontact boxing training session compared with submaximal treadmill running.

The aim of this study was to determine the energy expenditure of a 1-h noncontact boxing training session and to compare these results with the energy expenditure of a more conventional recreational activity such as running. Eight healthy males, accustomed to noncontact boxing training, were recruited for the study. Subjects underwent three tests: (i) a boxing training session in the laboratory during which energy expenditure was measured continuously using indirect calorimetry (BOXL), (ii) a boxing training session in a boxing studio during which heart rate was measured continuously (BOXS), and (iii) an incremental running test on the treadmill during which energy expenditure was measured continuously. The energy expenditure during 60 min of BOXL ranged between 2519 and 3079 kJ (2821 +/- 190 kJ). Seven of the 8 subjects had higher heart rates during BOXL compared with those during BOXS, suggesting that the subjects exercised at a slightly higher intensity during BOXL, possibly because of the "one on one" supervision. A typical boxing training session lasting 60 min causes a person to expend 2821 +/- 190 kJ x h(-1), the same amount of energy as someone running about 9 km in 60 min on the treadmill.

Adult↗

PubMed2003

TOX defines a conserved subfamily of HMG-box proteins.

BACKGROUND: HMG-box proteins are a large and diverse superfamily of architectural factors that share one or more copies of a sequence- and structurally-related DNA binding domain. These proteins can modify chromatin structure by bending and unwinding DNA. HMG-box proteins can be divided into two subfamilies based on whether they recognize DNA in a sequence-dependent or sequence-independent manner. We recently identified an HMG-box protein involved in T cell development, designated TOX, which is highly conserved in humans and mice. RESULTS: We show here that based on sequence alignment, TOX best fits into the sequence-independent HMG-box family. Three other human and murine predicted proteins are identified that share a common HMG-box domain with TOX, as well as other features. The gene encoding one of these additional family members has a distinct but overlapping pattern of tissue expression when compared to TOX. In addition, we identify genes encoding predicted TOX HMG-box subfamily members in pufferfish and mosquito. CONCLUSIONS: We have identified a novel subfamily of HMG-box proteins that is related to the recently described TOX protein. The highly conserved nature of the TOX family of proteins in humans and mice and differences in the pattern of expression between family members suggest non-overlapping functions of individual proteins. In addition, our data suggest that the TOX subtype of HMG-box domain first appeared in invertebrates, was duplicated in early vertebrates and likely took on new functions in mammalian species.

Amino Acid Sequence↗

PubMed1999

Acute intracranial boxing-related injuries in U.S. Marine Corps recruits: report of two cases.

Serious acute intracranial injuries from boxing are a recognized, albeit rare, event. Acute brain injuries such as concussion, hemorrhage, and contusion are easily recognized because of their rapid onset of neurological impairment. The sequelae of such injuries range from transient diminished cognitive function to irreversible brain damage and, on occasion, death. The more serious injuries are certainly minimized as a result of regulatory policy, improved medical awareness, and the use of safety equipment. The incidence of serious acute head injury in amateur boxing and noncompetitive boxing is lower than that found in the professional ranks. Our survey of instructional boxing in U.S. Marine Corps basic training during an 8-year period detected only three serious acute brain injuries incurred by approximately 180,000 participants, equating to one serious head injury per 60,000 participants. Serious head injuries constituted an extremely small percentage (0.3%) of the approximately 1,100 total boxing-related injuries surveyed during the period. We present two cases of serious acute brain injury incurred during noncompetitive boxing skills instruction as a part of U.S. Marine Corps basic training. A review of the data leads us to conclude that the risk of serious head injury in a well-supervised, instructional boxing program is relatively minimal. In any case, we recommend that any boxing be appropriately supervised and that specialized trauma care and an adequate transport mechanism to secure that care be readily available.

Acute Disease↗

PubMed1996

Interference of benzo[a]pyrene diol epoxide-deoxyguanosine adducts in a GC box with binding of the transcription factor Sp1.

Previous studies indicated that DNA adducts formed by the carcinogenic diol epoxide 7r,8t-dihydroxy-9t,10t-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene (BPDE) can increase the affinity of the transcription factor Sp1 for DNA sequences that are not normally specific binding sites. Whether adducts that form in the normal binding site, the GC box sequence, increase the affinity of Sp1 for the modified GC-box was not determined. Starting with a 23-nt sequence that contains two natural GC box sequences, site-specifically modified oligonucleotides were prepared with a single(+)-BPDE-deoxyguanosine adduct at one of three positions: the center of each GC-box or in between the two boxes. Four modified oligonucleotides were studied, two derived from cis addition of BPDE to the exocyclic amino group and two from trans addition. For three of these site-specifically modified oligonucleotides, there was a diminution in Sp1 affinity, whereas Sp1 binding to the fourth modified oligonucleotide was abolished. Furthermore, random modification of the oligonucleotide to a level of about 1 BPDE adduct per fragment slightly decreased the affinity for Sp1, and no evidence was found for a subpopulation of molecules with high affinity. These findings suggest that BPDE modification of the GC box does not lead to an increased affinity for Sp1. This is consistent with a model in which a BPDE-induced bend in the DNA mimics the conformation of the normal GC box:Sp1 complex, leading to high-affinity binding of Sp1 to non-Gc box sites.

7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide↗

PubMed1999

Two progesterone-dependent endometrial nuclear factors bind to an E-box in the rabbit uteroglobin gene promoter: involvement in tissue-specific transcription.

We studied the implications of progesterone-dependent transcription factors in the hormonal and tissue-specific induction of the uteroglobin gene (ug) in the rabbit endometrium. Previously, we have observed the interaction of two progesterone-dependent endometrial nuclear proteins (TRBPs) with sequences downstream from the ug TATA box. Using electrophoretic mobility shift assays (EMSA) we show here that TRBPs specifically interacted with an E-box localized almost immediately downstream from the ug TATA box. UV crosslinking of affinity-purified TRBPs to the radiolabeled oligonucleotide probe confirmed that these factors were proteins with molecular mass of about 40-50 kDa. Ferguson's analysis of the Mr of the DNA-TRBP complexes suggested that TRBPs interacted with the E-box either as homo- or heterodimers. This interaction did not result in detectable bending of the DNA. EMSA analysis with nuclear extracts from different rabbit tissues suggested that TRBPs might be endometrium-specific nuclear factors. Involvement of the E-box in the tissue-specific transcription from the ug promoter was assessed by transient expression experiments using different cell lines transfected with a reporter gene driven by the ug promoter which contained either the intact E-box or a mutated version that completely abolished its interaction with TRBPs. These experiments indicated that, in all cell lines of nonendometrial lineage, destruction of the E-box increased transcription from the ug promoter, whereas in two cell lines of endometrial origin this mutation either had no appreciable effect or slightly reduced the transcription from the promoter. Thus, this E-box and endometrial helix-loop-helix proteins might be involved in the hormonal and tissue-specific regulation of ug transcription.

Animals↗

PubMed2000

Growth state-dependent binding of USF-1 to a proximal promoter E box element in the rat plasminogen activator inhibitor type 1 gene.

Induced PAI-1 gene expression in renal epithelial (NRK-52E, clone EC-1) cells occurs as part of the immediate-early response to serum. PAI-1 transcripts are maximally expressed early in G(1) (within 4 h of serum addition to quiescent EC-1 cells) and then subsequently decline to basal levels prior to entry into DNA synthetic phase. Comparative analysis of PAI-1 mRNA abundance and de novo-synthesized thiolated RNA in quiescent cells, as well as at 4 h (early G(1)) and 20 h (late G(2)) postserum addition, in conjunction with RNA decay measurements indicated that PAI-1 gene regulation upon growth activation was predominantly transcriptional. An E box motif (CACGTG), important in the induced expression of some growth state-dependent genes, mapped to nucleotides -160 to -165 upstream of the transcription start site in the PAI-1 proximal promoter. Mobility-shift assessments, using a 18-bp deoxyoligonucleotide construct containing the E box within the context of PAI-1-specific flanking sequences, confirmed binding of EC-1 nuclear protein(s) to this probe and, specifically, to the E box hexanucleotide site. The specificity of this protein-probe interaction was verified by competition analyses with double-stranded DNA constructs that included E box deoxyoligonucleotides with non-PAI-1 flanking bases, mutant E box sequences incapable of binding NRK nuclear proteins, and unrelated (i.e., AP-1) target motifs. Extract immunodepletion and supershift/complex-blocking experiments identified one PAI-1 E box-binding protein to be upstream stimulatory factor-1 (USF-1), a member of the HLH family of transcription factors. Mutation of the CACGTG site to TCCGTG in an 18-bp PAI-1 probe inhibited the formation of USF-1-containing complexes confirming that an intact E box motif at -160 to -165 bp in the PAI-1 promoter and, in particular, the CA residues at -165 and -164 are essential for USF-1 binding. Incorporation of this 2 bp change into a reporter construct containing 764 bp of the proximal PAI-1 "promoter" ligated to a CAT gene effectively reduced (by 74%) CAT activity in cycling cells. An intact E box motif at nucleotides -160 to -165 in the PAI-1 promoter, thus, is an important functional element in the regulation of PAI-1 transcriptional activity in renal cells.

Animals↗

PubMed1996

Differential binding of HMG1, HMG2, and a single HMG box to cisplatin-damaged DNA.

The HMG box domain is a DNA binding domain present in the nonhistone chromosomal proteins HMG1 and HMG2 and in other proteins involved in the regulation of gene expression. Previous studies have demonstrated that HMG1 and HMG2 bind with high affinity to DNA modified with the cancer chemotherapeutic drug cisplatin (CDDP). In this report, we compare the binding of full-length HMG1 and HMG2 and the HMG boxes present in these proteins to that of CDDP-DNA. Complexes between HMG1, HMG2, or HMG Box A + B and CDDP-DNA were stable at > or = 500 mM salt, while complexes between a single HMG box and CDDP-DNA exhibited decreased stability. Analysis of a series of HMG1 Box A mutant constructs revealed different affinities for CDDP-DNA. Two constructs containing a Phe to Ala substitution at position 19 and a Tyr to Gly substitution at position 71, are noteworthy; these peptides exhibited reduced affinity for CDDP-DNA. We have generated a structure of HMG1 Box A and used it, along with the results of our binding studies, to model its interaction with CDDP-DNA. HMG1 Box A binds in the minor groove of CDDP-DNA, in agreement with earlier studies. Our model predicts that Tyr71 partially intercalates and forms an H bond with the sugar-phosphate backbone. The model also suggests that Phe 19 does not directly interact with DNA, and hence an Ala substitution at position 19 may alter protein structure. This model should provide a framework for future studies examining HMG Box-DNA interactions.

Amino Acid Sequence↗

PubMed2002

A conserved F-box gene with unusual transcript localization.

Drosophila partner of paired ( ppa), which encodes an F-box protein that targets the Pax transcription factor Paired (Prd) for degradation, has the striking property that its mRNA is expressed in a striped pattern with a characteristic registration relative to the striped expression of prd in early embryos. Localized expression of F-box genes was not expected because F-box proteins generally have multiple substrates. We hypothesize that the patterned mRNA expression of Drosophila and zebrafish ppa homologs may reflect constraints resulting from the localized expression of their degradation substrates. To begin to test this idea, we wished to determine whether patterned mRNA expression is commonly observed among F-box genes, or whether it might be peculiar to ppa and its homologs, or even specific to Drosophila. We examined embryonic expression of all predicted F-box genes in Drosophila and found that mRNAs of 21 out of 23 predicted F-box genes are expressed uniformly in early Drosophila embryos, whereas ppa and CG4911 mRNAs are patterned, CG4911 being expressed at the positions of gastrulation folds. We also identified and tested expression of ppa in zebrafish, which has two highly conserved homologs, ppaA and ppaB, and found that both are expressed during embryogenesis and have enriched mRNA expression in regions including the neural tube, the head, and the fin buds. Despite being unusual in having localized transcripts, we found that the Drosophila and zebrafish homologs interact with the expected Drosophila components of the cellular degradation machinery - Skp1 (SkpA) and Rbx1 (Roc1a) - suggesting that the Ppa proteins are indeed functional F-box proteins. We conclude that patterning of ppa mRNA could reflect a constraint on ppa function that is not common among F-box genes. Electronic supplementary material to this paper can be obtained by using the Springer LINK server located at http://dx.doi.org/10.1007/s00427-002-0222-7.

Amino Acid Sequence↗

PubMed1995

Conservation of the T-box gene family from Mus musculus to Caenorhabditis elegans.

Recently, a novel family of genes with a region of homology to the mouse T locus, which is known to play a crucial, and conserved, role in vertebrate development, has been discovered. The region of homology has been named the T-box. The T-box domain of the prototypical T locus product is associated with sequence-specific DNA binding activity. In this report, we have characterized four members of the T-box gene family from the nematode Caenorhabditis elegans. All lie in close proximity to each other in the middle of chromosome III. Homology analysis among all completely sequenced T-box products indicates a larger size for the conserved T-box domain (166 to 203 residues) than previously reported. Phylogenetic analysis suggests that one C. elegans T-box gene may be a direct ortholog of the mouse Tbx2 and Drosophila omb genes. The accumulated data demonstrate the ancient nature of the T-box gene family and suggest the existence of at least three separate T-box-containing genes in a common early metazoan ancestor to nematodes and vertebrates.

Amino Acid Sequence↗

PubMed2005

The effect of box preparation on the strength of glass fiber-reinforced composite inlay-retained fixed partial dentures.

STATEMENT OF PROBLEM: Nonstandardized box dimensions for inlay-retained fixed partial dentures (FPDs) may result in uneven distribution of the forces on the connector region of such restorations. PURPOSE: The objective of this in vitro study was to evaluate the effect of box dimensions on the initial and final failure strength of inlay-retained fiber-reinforced composite (FRC) FPDs. MATERIAL AND METHODS: Twenty-one inlay-retained FPDs were prepared using FRC (everStick) frameworks with unidirectional fiber reinforcement between mandibular first premolars and first molars. Boxes were prepared using conventional inlay burs (Cerinlay), and small and large ultrasonic tips (SONICSYS approx). Box dimensions were measured after preparation with a digital micrometer. All restorations were subjected to thermal cycling (6000 cycles, 5 degrees C-55 degrees C). Fracture testing was performed in a universal testing machine (1 mm/min). Acoustic emission signals were monitored during loading of the specimens. Initial and final fracture strength values (2-way ANOVA, Bonferroni post hoc tests, alpha =.05) and failure types (Fisher exact test) were statistically compared for each group. RESULTS: Significant differences (P =.0146 and P =.0086) were observed between the groups in the dimensions of the boxes prepared using conventional burs buccolingually (2.8-3.0 mm in molars, 3.1-4.3 mm in premolars) and the small size (2.5-2.9, 2.9-3.8 mm) or large size (2.6-3.8, 3.2-4.9 mm) ultrasonic tips for the premolars and the molars, respectively. No significant differences were found at the initial and final failures between the conventionally prepared group (842 +/- 267 N, 1161 +/- 428 N) and those prepared with either small (1088 +/- 381 N, 1320 +/- 380 N) or large ultrasonic tips (1070 +/- 280 N, 1557 +/- 321 N), respectively. The failure analysis demonstrated no significant difference in failure types but predominant delamination of the veneering resin (85%) in all experimental groups. According to acoustic emission tests, a higher energy level was required for final failure of the FRC FPDs with boxes finished using small ultrasonic tips. CONCLUSION: Standardized box dimensions showed no significant effect on fracture strength at either initial or final failure of the fiber-reinforced FPDs. The FRC FPDs with boxes refined with small ultrasonic burs required a greater energy level before failure. The type of failure observed after the fracture tests was primarily delamination of the veneering resin.

Acoustics↗

PubMed1997

Effect of periodic box size on aqueous molecular dynamics simulation of a DNA dodecamer with particle-mesh Ewald method.

The particle-mesh Ewald (PME) method is considered to be both efficient and accurate for the evaluation of long-range electrostatic interactions in large macromolecular systems being studied by molecular dynamics simulations. This method assumes "infinite" periodic boundary conditions resembling the symmetry of a crystal environment. Can such a "solid-state" method accurately portray a macromolecular solute such as DNA in solution? To address this issue, we have performed three 1500-ps PME molecular dynamics (MD) simulations, each with a different box size, on the d(CGCGA6CG)-(CGT6CGCG) DNA dodecamer. The smallest box had the DNA solvated by a layer of water molecules of at least 5 A along each orthogonal direction. The intermediate size box and the largest box had the DNA solvated by a layer of water molecules of at least 10 A and 15 A, respectively, along each orthogonal direction. The intermediate size box in the present study is similar to the box size currently chosen by most workers in the field. Based on a comparison of RMSDs and curvature for this single DNA dodecamer sequence, the larger two box sizes do not appear to afford any extra benefit over the smallest box. The implications of this finding are briefly discussed.

Base Sequence↗

PubMed2000

Increased xylanase production in Streptomyces lividans after replacement of the signal peptide: dependence on box and inverted repeat sequence.

The signal peptide of the xylanase A gene of Streptomyces lividans was replaced by the signal sequence of the cellulase A preceded by a 57 nucleotides (nt) upstream sequence. This latter contains a 5 nt inverted repeat (5'-TGGGAACGCTCCCA). The 3'-end of the inverted repeat contains a 5 nt box (TCCCA), which is complementary to the 16S rRNA of S. lividans. The effects on the production of xylanase resulting from deletions in the inverted repeat and from variations in the length of the box are shown. Removal of the inverted repeat and box decreased the xylanase production by 75%. Increasing the complementarity of the box with the 16S rRNA to 17 nt decreased the production by 90%. A reduction in the length of the inverted repeat, and consequently in the box, from 5 to 4 nt decreased the production by 40%. Preserving the 4 nt inverted repeat but lengthening the box from 5 to 6 nt increased the production by 1.5-fold. Finally, removing the inverted repeat but introducing an 8 nt box increased the xylanase production by 1.9-fold which then averaged 2.3 g/l of xylanase. The most efficient boxes contained 6-8 nt and were located between 14 and 19 nt downstream from the first initiation codon.

Clone Cells↗

PubMed2001

The KEN box regulates Clb2 proteolysis in G1 and at the metaphase-to-anaphase transition.

Clb2 mitotic cyclin inhibits cell cycle progression by preventing mitotic exit and DNA synthesis. To allow cell cycle progression, Clb2 proteolysis is triggered by Cdc20 during the metaphase-to-anaphase (M-A) transition and by Hct1 during mitotic exit and G1 [1-6]. A cis element called the destruction box is required for this proteolysis [7-11]. Recently, an additional cis element called the "KEN box" was also shown to be required for proteolysis of human CDC20 and Securin [3,12]. Using a novel color assay, we show that a Clb2 KEN box is required to target a fusion protein containing the first 124 amino acids of Clb2 for proteolysis. We further show that full-length Clb2 bearing mutations in the KEN box is degraded efficiently during the M-A transition, but poorly during G1. If the destruction box of Clb2 is mutated in combination with mutation of the KEN box, then this form of Clb2 is more stable than Clb2 bearing either mutation by itself during both M-A and G1. Our results show that the KEN box and the destruction box act together during both M-A and G1 to regulate Clb2 proteolysis.

Anaphase↗

PubMed2004

Cell cycle-regulated recognition of the destruction box of cyclin B by the APC/C in Xenopus egg extracts.

Substrates for mitotic proteolysis such as cyclin B have a 9 residue destruction motif, the destruction box (D-box). To identify the receptor that specifically binds the D-box, we used affinity chromatography with immobilized D-box matrices. We find that the APC/C from Xenopus egg extracts binds to the D-box of cyclin B, whereas Fizzy (Cdc20) does not. Mutations in the D-box abolished this interaction. We show that this binding is regulated in the cell cycle, such that the APC/C from egg extracts in interphase does not bind to the D-box matrix. Our results suggest that the APC/C forms a stable interaction with the D-box of its substrates in a cell cycle-dependent manner.

Animals↗

PubMed1993

Binding of transcription factor Sp1 to GC box DNA revealed by footprinting analysis: different contact of three zinc fingers and sequence recognition mode.

Transcription factor Sp1 has three tandem repeats of a Cys2His2-type zinc finger motif and specifically binds to GC box DNA. We investigated the interaction of Sp1 with GC box DNA by several footprinting techniques. Methylation of four guanine bases in the sequence 5'-GGGCG-3' is strongly protected by Sp1 binding, whereas a guanine base flanked at the 5' end by the above sequence is extremely hypermethylated. Methylation interference experiments explicitly show that four guanine bases from the guanine-rich strand, and one from the cytosine-rich strand, in the sequence 5'-GGGCG-3' are crucially required for GC box recognition by Sp1. In footprinting using the 1,10-phenanthroline-copper complex, binding of Sp1 clearly alters the cleavage patterns by the metal complex. Footprints of the protein did not cover the full length of each GC box sequence, and the protein strongly masked scission in the sequence 5'-GCGG(A/G)(G/A)-3'. In cleavage of GC box DNA by the bleomycin-iron complex, Sp1 binding induces new cutting at a 5'-GA-3' site within the box. The results indicate that (i) the three zinc fingers do not contribute equivalently to the binding of Sp1 to the GC box, namely, important base contacts arise from the second and third fingers, and (ii) the protein binding induces local but significant structural distortion of the 3' region of the guanine-rich strand in the GC box. These features are clearly distinct from those of Zif268 and Krox20, which are three-zinc-finger proteins closely related to Sp1.

Amino Acid Sequence↗

PubMed2006

The Prp19 U-box crystal structure suggests a common dimeric architecture for a class of oligomeric E3 ubiquitin ligases.

Prp19 is an essential splicing factor and a member of the U-box family of E3 ubiquitin ligases. Prp19 forms a tetramer via a central coiled-coil domain. Here, we show the U-box domain of Prp19 exists as a dimer within the context of the Prp19 tetramer. A high-resolution structure of the homodimeric state of the Prp19 U-box was determined by X-ray crystallography. Mutation of the U-box dimer interface abrogates U-box dimer formation and is lethal in vivo. The structure of the U-box dimer enables construction of a complete model of Prp19 providing insights into how the tetrameric protein functions as an E3 ligase. Finally, comparison of the Prp19 U-box homodimer with the heterodimeric complex of BRCA1/BARD1 RING-finger domains uncovers a common architecture for a family of oligomeric U-box and RING-finger E3 ubiquitin ligases, which has mechanistic implications for E3 ligase-mediated polyubiquitination and E4 polyubiquitin ligases.

Amino Acid Sequence↗