Structural studies of postentry restriction factors reveal antiparallel dimers that enable avid binding to the HIV-1 capsid lattice

Goldstone, David C.; Walker, P.A.; Calder, Lesley J.; Coombs, P.J.; Kirkpatrick, Joshua; Ball, Neil J.; Hilditch, Laura; Yap, Melvyn W.; Rosenthal, Peter B.; Stoye, Jonathan P.; Taylor, Ian A.

doi:10.1073/pnas.1402448111

Cited by 94 publications

(161 citation statements)

References 42 publications

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“…These profiles are very similar to those reported for the coiled‐coil region‐containing fragments of TRIM5α and TRIM20 (Goldstone et al , 2014; Weinert et al , 2015). Remarkably, the maximum dimension of the envelope for the TRIM25 RBCC construct (183 Å) is not much longer than that for the isolated CC structure of TRIM25 (170 Å) and comparable to the lengths of the TRIM5α BCC (180 Å) and TRIM20 CC/B30.2 constructs (167 Å) (Fig EV3) (Goldstone et al , 2014; Sanchez et al , 2014; Weinert et al , 2015). Furthermore, dimeric TRIM25 RBCC has a cross‐sectional radius of 31 Å, which is very similar to that of the tetrameric TRIM32 RBCC (32 Å).…”

Section: Resultssupporting

confidence: 87%

“…Furthermore, dimeric TRIM25 RBCC has a cross‐sectional radius of 31 Å, which is very similar to that of the tetrameric TRIM32 RBCC (32 Å). These observations suggest a model for the structure of the TRIM25 RBCC fragment in which the RING and B‐box domains might fold back across the coiled‐coil in a fashion similar to that observed in the crystal structure of the TRIM5α BCC fragment, where each B‐box, on either side of the CC stem, packs back onto the helices (Fig EV3) (Goldstone et al , 2014). In contrast, the TRIM32 RBCC construct is the longest with a D max of 243 Å and a particle central diameter of ~56 Å that can easily accommodate the width of 2 coiled‐coil stems (~18 Å from the structure of TRIM5α).…”

Section: Resultsmentioning

confidence: 61%

“…The crystal structures of the coiled‐coil regions of TRIM5α, TRIM20, TRIM25 and TRIM69 all show an anti‐parallel dimer for this region, and based on sequence conservation, this behaviour might be a general property of the TRIM family (Goldstone et al , 2014; Li et al , 2014; Sanchez et al , 2014; Weinert et al , 2015). In support of this suggestion, inclusion of the CC region mediates further self‐association and we detect a single tetrameric species with a molecular weight of ~160 kDa for a fragment of TRIM32 (RBCC) in which the dimeric RING/B‐box construct is extended to include the coiled‐coil (Fig 1C).…”

Section: Resultsmentioning

confidence: 99%

“…Though structural details of the mechanistic features that could explain oligomerization‐dependent activity are currently sparse, coiled‐coil‐mediated RING dimerization and subsequent stabilization of a closed E2~ubiquitin intermediate could explain this observation. However, recent structural studies showed that some TRIMs, and possibly all, adopt an antiparallel coiled‐coil orientation (Goldstone et al , 2014; Li et al , 2014; Sanchez et al , 2014; Weinert et al , 2015). Such an anti‐parallel arrangement locates the N‐terminal RING domains at opposite ends of the molecule implying that a dimeric RING arrangement may require formation of higher order TRIM complexes.…”

Section: Introductionmentioning

confidence: 99%

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Functional role of TRIM E3 ligase oligomerization and regulation of catalytic activity

et al. 2016

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TRIM E3 ubiquitin ligases regulate a wide variety of cellular processes and are particularly important during innate immune signalling events. They are characterized by a conserved tripartite motif in their N‐terminal portion which comprises a canonical RING domain, one or two B‐box domains and a coiled‐coil region that mediates ligase dimerization. Self‐association via the coiled‐coil has been suggested to be crucial for catalytic activity of TRIMs; however, the precise molecular mechanism underlying this observation remains elusive. Here, we provide a detailed characterization of the TRIM ligases TRIM25 and TRIM32 and show how their oligomeric state is linked to catalytic activity. The crystal structure of a complex between the TRIM25 RING domain and an ubiquitin‐loaded E2 identifies the structural and mechanistic features that promote a closed E2~Ub conformation to activate the thioester for ubiquitin transfer allowing us to propose a model for the regulation of activity in the full‐length protein. Our data reveal an unexpected diversity in the self‐association mechanism of TRIMs that might be crucial for their biological function.

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Section: Resultssupporting

confidence: 87%

Section: Resultsmentioning

confidence: 61%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Functional role of TRIM E3 ligase oligomerization and regulation of catalytic activity

et al. 2016

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“…7c, d), based on three structural domain features: (i) the B-box 2 domain facilitates higher-order assembly 156,157 , (ii) the Coiled-coil region facilitates the antiparallel dimerization of TRIMs 183,185 , as shown in recent structures comprising the Coiled-coil region with B-box 2 (ref 186 ) and PRY-SPRY domains 187 ( Fig. 7c), and (iii) the L2 linker from the C-terminal end of the Coiled-coil domain mediates positioning of the substrate-binding domain 188 in the vicinity of proximal RING domain 187 , thereby providing the close distance for substrate ubiquitination.…”

Section: Trims Higher-order Oligomer Formationsmentioning

confidence: 99%

Structural insights into protein-protein interactions governing regulation in transcription initiation and ubiquitination

Anandapadamanaban¹

2015

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Front cover:Surface representation of the protein-protein complexes of E2~Ub-TRIM E3 ligase, which I have embellished with interacting proteins/domains in a range of colors.The author apologizes to those whose work could not be cited directly as original research articles but rather cited the recent reviews, due to space limitations.All previously published original peer reviewed articles are reprinted with permissions from the publisher.© Copyright 2015 Madhanagopal Anandapadamanaban, unless otherwise mentioned. Linkoping studies in Science and Technology. Dissertation No. 1694 Printed in Sweden by LiU-Tryck, 2015 Madhanagopal Anandapadamanaban Structural insights into protein-protein interactions governing regulation in transcription initiation and ubiquitination AbstractVirtually every aspect of the cellular processes in eukaryotes requires that the interactions between protein molecules are well coordinated in different regulatory pathways. Any protein dysfunction involved in these regulatory pathways might lead to various pathological conditions. Understanding the structural and functional peculiarities of these proteins molecular machineries will help in formulating structure-based drug design.The first regulatory process studied here is the RNA polymerase-II mediated transcription of the eukaryotic protein-coding genes to produce mRNAs. This process requires the formation of the 'transcription initiation' by the assembly of Pre-Initiation Complex (PIC) formation at a core promoter region. Regulation at this initiation level is a key mechanism for the control of gene expression that governs cellular growth and differentiation. The transcription Factor IID (TFIID) is a conserved multiprotein general transcription factor with an essential role in nucleating the PIC formation, composed of TATA Binding Protein (TBP) and about 14 TBP Associated Factors (TAFs). The here presented crystal structure (1.97 Å) of TBP bound to TAND1 and TAND2 domains from TAF1 reveals a detailed molecular pattern of interactions involving both transcriptionally activating and repressing regions in TBP, thereby uncovering central principles for anchoring of TBP-binding motifs. Together with NMR and cellular analysis, this work provides the structural basis of competitive binding with TFIIA to modulate TBP in promoter recognition.In eukaryotes, another fundamental mechanism in the regulation of cellular physiology is the post-translational modification of substrate proteins by ubiquitin, termed 'ubiquitination'. Important actors in this mechanism are the ubiquitin-ligases (E3s) that culminate the transfer of ubiquitin to the substrate and govern the specificity of this system. One E3 ligase in particular, TRIM21, defines a subgroup of the Tripartite Motif (TRIM) family, which belongs to the major RING-type of E3 ubiquitin ligases, and plays an important role in pathogenesis of autoimmunity by mediating ubiquitination of transcription factors. The crystal structure (2.86 Å) of the RING domain from TRIM21 ...

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TRAF trimers form immune signalling networks viaRING domain dimerization

et al. 2022

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For many inflammatory cytokines, the response elicited is dependent on the recruitment of the tumour necrosis factor receptor‐associated factor (TRAF) family of adaptor proteins. All TRAF proteins have a trimeric C‐terminal TRAF domain, while at the N‐terminus most TRAFs have a RING domain that forms dimers. The symmetry mismatch of the N‐ and C‐terminal halves of TRAF proteins means that when receptors cluster, it is presumed that RING dimers connect TRAF trimers to form a network. Here, using purified TRAF6 proteins, we provide direct evidence in support of this model, and we show that TRAF6 trimers bind Lys63‐linked ubiquitin chains to promote their processive assembly. This study provides critical evidence in support of TRAF trimers as key players in signalling.

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Structural studies of postentry restriction factors reveal antiparallel dimers that enable avid binding to the HIV-1 capsid lattice

Cited by 94 publications

References 42 publications

Functional role of TRIM E3 ligase oligomerization and regulation of catalytic activity

Functional role of TRIM E3 ligase oligomerization and regulation of catalytic activity

Structural insights into protein-protein interactions governing regulation in transcription initiation and ubiquitination

TRAF trimers form immune signalling networks viaRING domain dimerization

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