scholarly journals TRIM protein domain topology and implications for antiviral immunity

2014 ◽  
Vol 70 (a1) ◽  
pp. C243-C243
Author(s):  
David Jacques ◽  
Cy Jeffries ◽  
Matthew Caines ◽  
Michael Lammers ◽  
Donna Mallery ◽  
...  
Keyword(s):  
Domain Architecture ◽  
Coiled Coil ◽  
Antiviral Immunity ◽  
Protein Domain ◽  
Titration Calorimetry ◽  
Protein Chain ◽  
Trim Protein ◽  
Tripartite Motif ◽  
Trim Proteins ◽  
Terminal Domains

The tripartite motif (TRIM) proteins are a large family of >100 members, several of which have important roles in antiviral immunity and innate immune signaling. TRIM5α associates with incoming HIV-1 capsids, interfering with controlled disassembly and targeting them for degradation by the proteasome. TRIM21 is a cytosolic antibody receptor, which also targets incoming viral capsids for proteasomal degradation. TRIM25 is also involved in innate immunity, being essential for the ubiquitination of RIG-I. Recent positive selection analysis has predicted another 10 TRIM proteins with antiviral activity. Despite the fact that TRIM5α, 21 and 25 play key roles in antiviral protection, their mechanism of action is incompletely understood. All three proteins share a similar domain architecture, comprising a RING, B Box, coiled coil and PRYSPRY domains. The RING domains are responsible for ubiquitin ligase activity, while the PRYSPRY domains determine target specificity. We have used a combination of crystallography and SAXS to generate the first complete model for a TRIM protein structure. Crystallographic studies of TRIM25 reveal a central elongated coiled-coil domain with an unusual right-handed twist. The dimer formed by the coiled-coil is antiparallel but is followed by additional helices that reverse the direction of the protein chain. This structure suggests that the N-terminal domains of each monomer are separated but the C terminal domains are maintained in proximity. Multi-angle light scattering (MALS), isothermal titration calorimetry (ITC) and SAXS analysis confirms that this dimer structure is present in solution. Furthermore, scattering studies on the tripartite motif of TRIM21, comprising RING, B Box and coiled-coil, demonstrate that the first two domains of each monomer are held 150-200 Å apart. Finally, SAXS measurement of a complex between intact TRIM21 and its ligand, IgG Fc, provides the first empirical structure of a complete TRIM protein.

Functional interactions between ubiquitin E2 enzymes and TRIM proteins

2011 ◽  
Vol 434 (2) ◽  
pp. 309-319 ◽  
Author(s):  
Luisa M. Napolitano ◽  
Ellis G. Jaffray ◽  
Ronald T. Hay ◽  
Germana Meroni
Keyword(s):  
Coiled Coil ◽  
Specific Interactions ◽  
E3 Ligases ◽  
Cellular Processes ◽  
Coiled Coil Region ◽  
Physiological Relevance ◽  
Tripartite Motif ◽  
E2 Enzymes ◽  
Specific Reactions ◽  
Trim Proteins

The TRIM (tripartite motif) family of proteins is characterized by the presence of the tripartite motif module, composed of a RING domain, one or two B-box domains and a coiled-coil region. TRIM proteins are involved in many cellular processes and represent the largest subfamily of RING-containing putative ubiquitin E3 ligases. Whereas their role as E3 ubiquitin ligases has been presumed, and in several cases established, little is known about their specific interactions with the ubiquitin-conjugating E2 enzymes or UBE2s. In the present paper, we report a thorough screening of interactions between the TRIM and UBE2 families. We found a general preference of the TRIM proteins for the D and E classes of UBE2 enzymes, but we also revealed very specific interactions between TRIM9 and UBE2G2, and TRIM32 and UBE2V1/2. Furthermore, we demonstrated that the TRIM E3 activity is only manifest with the UBE2 with which they interact. For most specific interactions, we could also observe subcellular co-localization of the TRIM involved and its cognate UBE2 enzyme, suggesting that the specific selection of TRIM–UBE2 pairs has physiological relevance. Our findings represent the basis for future studies on the specific reactions catalysed by the TRIM E3 ligases to determine the fate of their targets.

scholarly journals Human Parainfluenza Virus 3 Phosphoprotein Is a Tetramer and Shares Structural and Interaction Features with Ebola Phosphoprotein VP35

Biomolecules ◽  
2021 ◽  
Vol 11 (11) ◽  
pp. 1603
Author(s):  
Joaquin Rodriguez Galvan ◽  
Brianna Donner ◽  
Cat Hoang Veseley ◽  
Patrick Reardon ◽  
Heather M. Forsythe ◽  
...  
Keyword(s):  
Protein Interactions ◽  
Ebola Virus ◽  
Domain Architecture ◽  
Coiled Coil ◽  
Host Protein ◽  
Parainfluenza Virus ◽  
Titration Calorimetry ◽  
Binding Motifs ◽  
Multiple Association ◽  
Human Parainfluenza Virus

The human parainfluenza virus 3 (HPIV3) poses a risk for pneumonia development in young children and immunocompromised patients. To investigate mechanisms of HPIV3 pathogenesis, we characterized the association state and host protein interactions of HPIV3 phosphoprotein (HPIV3 P), an indispensable viral polymerase cofactor. Sequence analysis and homology modeling predict that HPIV3 P possesses a long, disordered N-terminal tail (PTAIL) a coiled-coil multimerization domain (PMD), similar to the well-characterized paramyxovirus phosphoproteins from measles and Sendai viruses. Using a recombinantly expressed and purified construct of PMD and PTAIL, we show that HPIV3 P in solution is primarily an alpha-helical tetramer that is stable up to 60 °C. Pulldown and isothermal titration calorimetry experiments revealed that HPIV3 P binds the host hub protein LC8, and turbidity experiments demonstrated a new role for LC8 in increasing the solubility of HPIV3 P in the presence of crowding agents such as RNA. For comparison, we show that the multimerization domain of the Zaire Ebola virus phosphoprotein VP35 is also a tetramer and binds LC8 but with significantly higher affinity. Comparative analysis of the domain architecture of various virus phosphoproteins in the order Mononegavirales show multiple predicted and verified LC8 binding motifs, suggesting its prevalence and importance in regulating viral phosphoprotein structures. Our work provides evidence for LC8 binding to phosphoproteins with multiple association states, either tetrameric, as in the HPIV3 and Ebola phosphoproteins shown here, or dimeric as in rabies virus phosphoprotein. Taken together the data suggest that the association states of a virus-specific phosphoprotein and the complex formed by binding of the phosphoprotein to host LC8 are important regulators of viral function.

Abstract 218: The Role of Novel Tripartite Motif Proteins in Sarcolemmal Membrane Repair

2014 ◽  
Vol 115 (suppl_1) ◽  
Author(s):  
Liubov V Gushchina ◽  
Jenna Alloush ◽  
Sayak Bhattacharya ◽  
Zhaobin Xu ◽  
Eric X Beck ◽  
...  
Keyword(s):  
Membrane Damage ◽  
Coiled Coil ◽  
Cardiac Cells ◽  
Acute Injury ◽  
Membrane Repair ◽  
Repair Capacity ◽  
E3 Ligases ◽  
Tripartite Motif ◽  
Trim Proteins

Tripartite motif (TRIM) proteins are a superfamily of coiled-coil-containing RING E3 ligases that function in many cellular processes, particularly in membrane repair pathways. Mitsugumin 53 (MG53) also known as TRIM72, is primary expressed in skeletal muscle and heart. Our experimental data confirm that during membrane damage, MG53 translocates to the injury site and acts as a molecular glue to reseal the damage area. The role of MG53 in membrane repair has been demonstrated in both in vitro studies using molecular approaches and in vivo using rodent wild type and knockout models. Thus, our data indicate that recombinant human MG53 protein can be directly applied as a therapeutic agent to increase the membrane repair capacity of many cell types, including cardiomyocytes during acute injury or in chronic disease progression. However, the precise mechanism and potential partners by which MG53 executes its membrane repair function are not completely understood. On the basis of the global TRIM family protein alignment, we hypothesize that there are other TRIM proteins that, alone or together with MG53, may facilitate repair by targeting the site of an injury. Moreover, data from our lab demonstrated that MG53 and these TRIM proteins can form homo- and hetero-oligomeric assemblies due to the presence of the coiled-coil region in these proteins and, further, that this may be necessary for the active membrane resealing process. Using E. coli protein expression methodology we can generate and isolate new TRIM recombinant proteins and test if these protein complexes are effective when applied externally to cardiac and non-cardiac cells. These novel proteins will also be tested for their pharmacokinetic properties to determine their efficacy in both acute and chronic applications. Our studies should increase our knowledge of the mechanisms controlling cardiac membrane repair and also provide novel therapeutic targets.

scholarly journals Functional Replacement of the RING, B-Box 2, and Coiled-Coil Domains of Tripartite Motif 5α (TRIM5α) by Heterologous TRIM Domains

2006 ◽  
Vol 80 (13) ◽  
pp. 6198-6206 ◽  
Author(s):  
Xing Li ◽  
Yuan Li ◽  
Matthew Stremlau ◽  
Wen Yuan ◽  
Byeongwoon Song ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Coiled Coil ◽  
Chimeric Proteins ◽  
Immunodeficiency Virus ◽  
Tripartite Motif ◽  
Trim Proteins ◽  
Hiv 1 ◽  
Functional Replacement ◽  
Distant Relative

ABSTRACT Tripartite motif 5α (TRIM5α) restricts some retroviruses, including human immunodeficiency virus type 1 (HIV-1), from infecting the cells of particular species. TRIM5α is a member of the TRIM family of proteins, which contain RING, B-box, coiled-coil (CC), and, in some cases, B30.2(SPRY) domains. Here we investigated the abilities of domains from TRIM proteins (TRIM6, TRIM34, and TRIM21) that do not restrict HIV-1 infection to substitute for the domains of rhesus monkey TRIM5α (TRIM5αrh). The RING, B-box 2, and CC domains of the paralogous TRIM6 and TRIM34 proteins functionally replaced the corresponding TRIM5αrh domains, allowing HIV-1 restriction. By contrast, similar chimeras containing the components of TRIM21, a slightly more distant relative of TRIM5, did not restrict HIV-1 infection. The TRIM21 B-box 2 domain and its flanking linker regions contributed to the functional defectiveness of these chimeras. All of the chimeric proteins formed trimers. All of the chimeras that restricted HIV-1 infection bound the assembled HIV-1 capsid complexes. These results indicate that heterologous RING, B-box 2, and CC domains from related TRIM proteins can functionally substitute for TRIM5αrh domains.

scholarly journals TRIM29 in Cutaneous Squamous Cell Carcinoma

2021 ◽  
Vol 8 ◽  
Author(s):  
Che-Yuan Hsu ◽  
Teruki Yanagi ◽  
Hideyuki Ujiie
Keyword(s):  
Malignant Tumors ◽  
Coiled Coil ◽  
Dna Damage Signaling ◽  
Physiological Processes ◽  
Trim Protein ◽  
Coiled Coil Domain ◽  
Zinc Finger Motifs ◽  
Wide Range ◽  
Trim Proteins

Tripartite motif (TRIM) proteins play important roles in a wide range of cell physiological processes, such as signal transduction, transcriptional regulation, innate immunity, and programmed cell death. TRIM29 protein, encoded by the ATDC gene, belongs to the RING-less group of TRIM protein family members. It consists of four zinc finger motifs in a B-box domain and a coiled-coil domain, and makes use of the B-box domain as E3 ubiquitin ligase in place of the RING. TRIM29 was found to be involved in the formation of homodimers and heterodimers in relation to DNA binding; additional studies have also demonstrated its role in carcinogenesis, DNA damage signaling, and the suppression of radiosensitivity. Recently, we reported that TRIM29 interacts with keratins and FAM83H to regulate keratin distribution. Further, in cutaneous SCC, the expression of TRIM29 is silenced by DNA methylation, leading to the loss of TRIM29 and promotion of keratinocyte migration. This paper reviews the role of TRIM family proteins in malignant tumors, especially the role of TRIM29 in cutaneous SCC.

scholarly journals TRIM32 and Malin in Neurological and Neuromuscular Rare Diseases

Cells ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 820
Author(s):  
Lorena Kumarasinghe ◽  
Lu Xiong ◽  
Maria Adelaida Garcia-Gimeno ◽  
Elisa Lazzari ◽  
Pascual Sanz ◽  
...  
Keyword(s):  
Common Ancestor ◽  
Genetic Diseases ◽  
Ubiquitin Ligases ◽  
E3 Ubiquitin Ligases ◽  
Lafora Disease ◽  
C Terminus ◽  
Rare Genetic Diseases ◽  
Tripartite Motif ◽  
Trim Proteins ◽  
Ring E3

Tripartite motif (TRIM) proteins are RING E3 ubiquitin ligases defined by a shared domain structure. Several of them are implicated in rare genetic diseases, and mutations in TRIM32 and TRIM-like malin are associated with Limb-Girdle Muscular Dystrophy R8 and Lafora disease, respectively. These two proteins are evolutionary related, share a common ancestor, and both display NHL repeats at their C-terminus. Here, we revmniew the function of these two related E3 ubiquitin ligases discussing their intrinsic and possible common pathophysiological pathways.

scholarly journals Molecular basis for the fold organization and sarcomeric targeting of the muscle atrogin MuRF1

Open Biology ◽  
2014 ◽  
Vol 4 (3) ◽  
pp. 130172 ◽  
Author(s):  
Barbara Franke ◽  
Alexander Gasch ◽  
Dayté Rodriguez ◽  
Mohamed Chami ◽  
Muzamil M. Khan ◽  
...  
Keyword(s):  
Ubiquitin Ligase ◽  
Quaternary Structure ◽  
E3 Ubiquitin Ligase ◽  
Coiled Coil ◽  
Trim Protein ◽  
Muscle Catabolism ◽  
And Function ◽  
Helical Region ◽  
Structural Significance

MuRF1 is an E3 ubiquitin ligase central to muscle catabolism. It belongs to the TRIM protein family characterized by a tripartite fold of RING, B-box and coiled-coil (CC) motifs, followed by variable C-terminal domains. The CC motif is hypothesized to be responsible for domain organization in the fold as well as for high-order assembly into functional entities. But data on CC from this family that can clarify the structural significance of this motif are scarce. We have characterized the helical region from MuRF1 and show that, contrary to expectations, its CC domain assembles unproductively, being the B2- and COS-boxes in the fold (respectively flanking the CC) that promote a native quaternary structure. In particular, the C-terminal COS-box seemingly forms an α-hairpin that packs against the CC, influencing its dimerization. This shows that a C-terminal variable domain can be tightly integrated within the conserved TRIM fold to modulate its structure and function. Furthermore, data from transfected muscle show that in MuRF1 the COS-box mediates the in vivo targeting of sarcoskeletal structures and points to the pharmacological relevance of the COS domain for treating MuRF1-mediated muscle atrophy.

scholarly journals P029 TRIM 21 protects against ulcerative colitis and colitic cancer via smad7 inhibition

2020 ◽  
Vol 14 (Supplement_1) ◽  
pp. S146-S146
Author(s):  
K B Hahm
Keyword(s):  
Ulcerative Colitis ◽  
Coiled Coil ◽  
Type I ◽  
Typical Structure ◽  
Th17 Cell Differentiation ◽  
Bowel Diseases ◽  
Colitic Cancer ◽  
Β Receptor ◽  
Trim Proteins

Abstract Background Proteins of the tripartite motif-containing (TRIM) superfamily are critical in a variety of biological processes in either innate immunity or eliminating invading pathogens, by which had been implicated in pathogenesis of autoimmune diseases including inflammatory bowel diseases. The typical structure of TRIM proteins contains a RING motif in the N-terminal end, followed by a B-box motif, a coiled-coil domain and a B30.2/PRYSPRY region in the C-terminal end led to the regulation of TGF-β anti-inflammatory cytokines, by which TRIM21 has been reported to regulate IBD negatively through inhibiting Th1/Th17 cell differentiation. Methods Since antisense oligonucleotide targeting smad7 was withdrawn from clinical trial due to insufficient efficacy, in this study, we generated TRIM21 overexpressed cell lines to study the binding of TRIM21 to smad7 as well as the regulation of consequent TGF-β receptor. Results TRIM21 significantly binds to smad7 as well as repressed levels of TGF-b type I/II receptor. SBE-luc and 3TP-luc assay showed significantly decreased activities under TRIM21 + TGF-β. Since TRIM21 contains ubiquitin ligase, PRYSPRY, TRIM21 with TGF-β significantly decreased TGFRII via UPL. These in vitro evidences that TRIM21 significantly repressed TGF-β after binding smad7 were validated with DSS-induced colitis and colitic cancer model. TRIM21 was significantly decreased in DSS-induced ulcerative colitis, whereas ameliorated colitis showed significant restoration of TRIM21 Conclusion Leading to conclusion that loss of TRIM21 led to significant bout of IBD.

scholarly journals TRIM proteins in neuroblastoma

2019 ◽  
Vol 39 (12) ◽  
Author(s):  
Yonghu Xu ◽  
Zihan Zhang ◽  
Guofeng Xu
Keyword(s):  
High Risk ◽  
Tumor Suppressor ◽  
Solid Tumor ◽  
Molecular Mechanisms ◽  
Tumor Suppressor Proteins ◽  
Human Cancers ◽  
Tripartite Motif ◽  
Tumor In Childhood ◽  
Trim Proteins

Abstract Neuroblastoma (NB) is the most common extracranial solid tumor in childhood. Outcome for children with high-risk NB remains unsatisfactory. Accumulating evidence suggests that tripartite motif (TRIM) family proteins express diversely in various human cancers and act as regulators of oncoproteins or tumor suppressor proteins. This review summarizes the TRIM proteins involving in NB and the underlying molecular mechanisms. We expect these new insights will provide important implications for the treatment of NB by targeting TRIM proteins.

scholarly journals The Roles of TRIMs in Antiviral Innate Immune Signaling

2021 ◽  
Vol 11 ◽  
Author(s):  
Zhou Shen ◽  
Lin Wei ◽  
Zhi-bo Yu ◽  
Zhi-yan Yao ◽  
Jing Cheng ◽  
...  
Keyword(s):  
Immune Response ◽  
Lupus Erythematosus ◽  
Innate Immune ◽  
Innate Immune Responses ◽  
Cellular Functions ◽  
Trim Protein ◽  
Innate Immune Signaling ◽  
Viral Lifecycle ◽  
Trim Proteins ◽  
Viral Components

The Tripartite motif (TRIM) protein family, which contains over 80 members in human sapiens, is the largest subfamily of the RING-type E3 ubiquitin ligase family. It is implicated in regulating various cellular functions, including cell cycle process, autophagy, and immune response. The dysfunction of TRIMs may lead to numerous diseases, such as systemic lupus erythematosus (SLE). Lots of studies in recent years have demonstrated that many TRIM proteins exert antiviral roles. TRIM proteins could affect viral replication by regulating the signaling pathways of antiviral innate immune responses. Besides, TRIM proteins can directly target viral components, which can lead to the degradation or functional inhibition of viral protein through degradative or non-degradative mechanisms and consequently interrupt the viral lifecycle. However, new evidence suggests that some viruses may manipulate TRIM proteins for their replication. Here, we summarize the latest discoveries on the interactions between TRIM protein and virus, especially TRIM proteins’ role in the signaling pathway of antiviral innate immune response and the direct “game” between them.

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