Browse
Submit Data
Databases
API
Help

Dataset Information

33 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

SUMO Interacting Motifs: Structure and Function.

ABSTRACT: Small ubiquitin-related modifier (SUMO) is a member of the ubiquitin-related protein family. SUMO modulates protein function through covalent conjugation to lysine residues in a large number of proteins. Once covalently conjugated to a protein, SUMO often regulates that protein's function by recruiting other cellular proteins. Recruitment frequently involves a non-covalent interaction between SUMO and a SUMO-interacting motif (SIM) in the interacting protein. SIMs generally consist of a four-residue-long hydrophobic stretch of amino acids with aliphatic non-polar side chains flanked on one side by negatively charged amino acid residues. The SIM assumes an extended β-strand-like conformation and binds to a conserved hydrophobic groove in SUMO. In addition to hydrophobic interactions between the SIM non-polar core and hydrophobic residues in the groove, the negatively charged residues in the SIM make favorable electrostatic contacts with positively charged residues in and around the groove. The SIM/SUMO interaction can be regulated by the phosphorylation of residues adjacent to the SIM hydrophobic core, which provide additional negative charges for favorable electrostatic interaction with SUMO. The SUMO interactome consists of hundreds or perhaps thousands of SIM-containing proteins, but we do not fully understand how each SUMOylated protein selects the set of SIM-containing proteins appropriate to its function. SIM/SUMO interactions have critical functions in a large number of essential cellular processes including the formation of membraneless organelles by liquid-liquid phase separation, epigenetic regulation of transcription through histone modification, DNA repair, and a variety of host-pathogen interactions.

SUBMITTER: Yau TY

PROVIDER: S-EPMC8616421 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

SUMO junction-what's your function? New insights through SUMO-interacting motifs.

Project description:The small ubiquitin-like modifier, SUMO, can be covalently linked to specific proteins and many substrates carrying this modification have been identified. However, for some proteins, the role that SUMO modification imparts remains obscure. Our understanding of SUMO biology and function has been significantly advanced by the recent discovery of proteins and protein domains that contain SUMO-interacting motifs (SIMs), which interact non-covalently with SUMO. Unlike the motifs and domains that mediate ubiquitin binding, the diversity of SIMs seems limited. Nevertheless, SIMs have already increased our understanding of how SUMO affects DNA repair, transcriptional activation, nuclear body formation and protein turnover. This review takes a detailed look at how SIMs were identified, how they specifically bind to SUMO, their crucial roles in multi-step enzymatic processes, and how they direct the assembly and disassembly of dimeric and multimeric protein complexes.

| S-EPMC2002525 | biostudies-other

SUMO-interacting motifs of human TRIM5? are important for antiviral activity.

Project description:Human TRIM5? potently restricts particular strains of murine leukemia viruses (the so-called N-tropic strains) but not others (the B- or NB-tropic strains) during early stages of infection. We show that overexpression of SUMO-1 in human 293T cells, but not in mouse MDTF cells, profoundly blocks N-MLV infection. This block is dependent on the tropism of the incoming virus, as neither B-, NB-, nor the mutant R110E of N-MLV CA (a B-tropic switch) are affected by SUMO-1 overexpression. The block occurred prior to reverse transcription and could be abrogated by large amounts of restricted virus. Knockdown of TRIM5? in 293T SUMO-1-overexpressing cells resulted in ablation of the SUMO-1 antiviral effects, and this loss of restriction could be restored by expression of a human TRIM5? shRNA-resistant plasmid. Amino acid sequence analysis of human TRIM5? revealed a consensus SUMO conjugation site at the N-terminus and three putative SUMO interacting motifs (SIMs) in the B30.2 domain. Mutations of the TRIM5? consensus SUMO conjugation site did not affect the antiviral activity of TRIM5? in any of the cell types tested. Mutation of the SIM consensus sequences, however, abolished TRIM5? antiviral activity against N-MLV. Mutation of lysines at a potential site of SUMOylation in the CA region of the Gag gene reduced the SUMO-1 block and the TRIM5? restriction of N-MLV. Our data suggest a novel aspect of TRIM5?-mediated restriction, in which the presence of intact SIMs in TRIM5?, and also the SUMO conjugation of CA, are required for restriction. We propose that at least a portion of the antiviral activity of TRIM5? is mediated through the binding of its SIMs to SUMO-conjugated CA.

| S-EPMC3072370 | biostudies-literature

Contribution of SUMO-interacting motifs and SUMOylation to the antiretroviral properties of TRIM5α.

Project description:Recent findings suggested that the SUMO-interacting motifs (SIMs) present in the human TRIM5α (TRIM5α(hu)) protein play an important role in the ability of TRIM5α(hu) to restrict N-MLV. Here we explored the role of SIMs in the ability of rhesus TRIM5α (TRIM5α(rh)) to restrict HIV-1, and found that TRIM5α(rh) SIM mutants IL376KK (SIM1mut) and VI405KK (SIM2mut) completely lost their ability to block HIV-1 infection. Interestingly, these mutants also lost the recently described property of TRIM5α(rh) to shuttle into the nucleus. Analysis of these variants revealed that they are unable to interact with the HIV-1 core, which might explain the reason that these variants are not active against HIV-1. Furthermore, NMR titration experiments to assay the binding between the PRYSPRY domain of TRIM5α(rh) and the small ubiquitin-like modifier 1(SUMO-1) revealed no interaction. In addition, we examined the role of SUMOylation in restriction, and find out that inhibition of SUMOylation by the adenoviral protein Gam1 did not alter the retroviral restriction ability of TRIM5α. Overall, our results do not support a role for SIMs or SUMOylation in the antiviral properties of TRIM5α.

| S-EPMC3534947 | biostudies-literature

SUMO-interacting motifs (SIMs) in Polo-like kinase 1-interacting checkpoint helicase (PICH) ensure proper chromosome segregation during mitosis.

Project description:Polo-like kinase 1 (Plk1)-interacting checkpoint helicase (PICH) localizes at the centromere and is critical for proper chromosome segregation during mitosis. However, the precise molecular mechanism of PICH's centromeric localization and function at the centromere is not yet fully understood. Recently, using Xenopus egg extract assays, we showed that PICH is a promiscuous SUMO binding protein. To further determine the molecular consequence of PICH/SUMO interaction on PICH function, we identified 3 SUMO-interacting motifs (SIMs) on PICH and generated a SIM-deficient PICH mutant. Using the conditional expression of PICH in cells, we found distinct roles of PICH SIMs during mitosis. Although all SIMs are dispensable for PICH's localization on ultrafine anaphase DNA bridges, only SIM3 (third SIM, close to the C-terminus end of PICH) is critical for its centromeric localization. Intriguingly, the other 2 SIMs function in chromatin bridge prevention. With these results, we propose a novel SUMO-dependent regulation of PICH's function on mitotic centromeres.

| S-EPMC4993536 | biostudies-literature

Structural basis for the E3 ligase activity enhancement of yeast Nse2 by SUMO-interacting motifs.

Project description:Post-translational modification of proteins by ubiquitin and ubiquitin-like modifiers, such as SUMO, are key events in protein homeostasis or DNA damage response. Smc5/6 is a nuclear multi-subunit complex that participates in the recombinational DNA repair processes and is required in the maintenance of chromosome integrity. Nse2 is a subunit of the Smc5/6 complex that possesses SUMO E3 ligase activity by the presence of a SP-RING domain that activates the E2~SUMO thioester for discharge on the substrate. Here we present the crystal structure of the SUMO E3 ligase Nse2 in complex with an E2-SUMO thioester mimetic. In addition to the interface between the SP-RING domain and the E2, the complex reveals how two SIM (SUMO-Interacting Motif) -like motifs in Nse2 are restructured upon binding the donor and E2-backside SUMO during the E3-dependent discharge reaction. Both SIM interfaces are essential in the activity of Nse2 and are required to cope with DNA damage.

| S-EPMC8636563 | biostudies-literature

Insights into high affinity small ubiquitin-like modifier (SUMO) recognition by SUMO-interacting motifs (SIMs) revealed by a combination of NMR and peptide array analysis.

Project description:The small ubiquitin-like modifiers (SUMOs) regulate many essential cellular functions. Only one type of SUMO-interacting motif (SIM) has been identified that can extend the β-sheet of SUMO as either a parallel or an antiparallel strand. The molecular determinants of the bound orientation and paralogue specificity of a SIM are unclear. To address this question, we have conducted structural studies of SUMO1 in complex with a SUMO1-specific SIM that binds to SUMO1 with high affinity without post-translational modifications using nuclear magnetic resonance methods. In addition, the SIM sequence requirements have been investigated by peptide arrays in comparison with another high affinity SIM that binds in the opposing orientation. We found that antiparallel binding SIMs tolerate more diverse sequences, whereas the parallel binding SIMs prefer the more strict sequences consisting of (I/V)DLT that have a preference in high affinity SUMO2 and -3 binding. Comparison of two high affinity SUMO1-binding SIMs that bind in opposing orientations has revealed common SUMO1-specific interactions needed for high affinity binding. This study has significantly advanced our understanding of the molecular determinants underlining SUMO-SIM recognition.

| S-EPMC3270977 | biostudies-literature

Characterizing the N- and C-terminal Small ubiquitin-like modifier (SUMO)-interacting motifs of the scaffold protein DAXX.

Project description:DAXX is a scaffold protein with diverse roles that often depend upon binding SUMO via its N- and/or C-terminal SUMO-interacting motifs (SIM-N and SIM-C). Using NMR spectroscopy, we characterized the in vitro binding properties of peptide models of SIM-N and SIM-C to SUMO-1 and SUMO-2. In each case, binding was mediated by hydrophobic and electrostatic interactions and weakened with increasing ionic strength. Neither isolated SIM showed any significant paralog specificity, and the measured ?M range K(D) values of SIM-N toward both SUMO-1 and SUMO-2 were ?4-fold lower than those of SIM-C. Furthermore, SIM-N bound SUMO-1 predominantly in a parallel orientation, whereas SIM-C interconverted between parallel and antiparallel binding modes on an ms to ?s time scale. The differences in affinities and binding modes are attributed to the differences in charged residues that flank the otherwise identical hydrophobic core sequences of the two SIMs. In addition, within its native context, SIM-N bound intramolecularly to the adjacent N-terminal helical bundle domain of DAXX, thus reducing its apparent affinity for SUMO. This behavior suggests a possible autoregulatory mechanism for DAXX. The interaction of a C-terminal fragment of DAXX with an N-terminal fragment of the sumoylated Ets1 transcription factor was mediated by SIM-C. Importantly, this interaction did not involve any direct contacts between DAXX and Ets1, but rather was derived from the non-covalent binding of SIM-C to SUMO-1, which in turn was covalently linked to the unstructured N-terminal segment of Ets1. These results provide insights into the binding mechanisms and hence biological roles of the DAXX SUMO-interacting motifs.

| S-EPMC3103359 | biostudies-literature

Nup358 binds to AGO proteins through its SUMO-interacting motifs and promotes the association of target mRNA with miRISC.

Project description:MicroRNA (miRNA)-guided mRNA repression, mediated by the miRNA-induced silencing complex (miRISC), is an important component of post-transcriptional gene silencing. However, how miRISC identifies the target mRNA in vivo is not well understood. Here, we show that the nucleoporin Nup358 plays an important role in this process. Nup358 localizes to the nuclear pore complex and to the cytoplasmic annulate lamellae (AL), and these structures dynamically associate with two mRNP granules: processing bodies (P bodies) and stress granules (SGs). Nup358 depletion disrupts P bodies and concomitantly impairs the miRNA pathway. Furthermore, Nup358 interacts with AGO and GW182 proteins and promotes the association of target mRNA with miRISC A well-characterized SUMO-interacting motif (SIM) in Nup358 is sufficient for Nup358 to directly bind to AGO proteins. Moreover, AGO and PIWI proteins interact with SIMs derived from other SUMO-binding proteins. Our study indicates that Nup358-AGO interaction is important for miRNA-mediated gene silencing and identifies SIM as a new interacting motif for the AGO family of proteins. The findings also support a model wherein the coupling of miRISC with the target mRNA could occur at AL, specialized domains within the ER, and at the nuclear envelope.

| S-EPMC5286382 | biostudies-literature

Disruption of PML nuclear bodies is mediated by ORF61 SUMO-interacting motifs and required for varicella-zoster virus pathogenesis in skin.

Project description:Promyelocytic leukemia protein (PML) has antiviral functions and many viruses encode gene products that disrupt PML nuclear bodies (PML NBs). However, evidence of the relevance of PML NB modification for viral pathogenesis is limited and little is known about viral gene functions required for PML NB disruption in infected cells in vivo. Varicella-zoster virus (VZV) is a human alphaherpesvirus that causes cutaneous lesions during primary and recurrent infection. Here we show that VZV disrupts PML NBs in infected cells in human skin xenografts in SCID mice and that the disruption is achieved by open reading frame 61 (ORF61) protein via its SUMO-interacting motifs (SIMs). Three conserved SIMs mediated ORF61 binding to SUMO1 and were required for ORF61 association with and disruption of PML NBs. Mutation of the ORF61 SIMs in the VZV genome showed that these motifs were necessary for PML NB dispersal in VZV-infected cells in vitro. In vivo, PML NBs were highly abundant, especially in basal layer cells of uninfected skin, whereas their frequency was significantly decreased in VZV-infected cells. In contrast, mutation of the ORF61 SIMs reduced ORF61 association with PML NBs, most PML NBs remained intact and importantly, viral replication in skin was severely impaired. The ORF61 SIM mutant virus failed to cause the typical VZV lesions that penetrate across the basement membrane into the dermis and viral spread in the epidermis was limited. These experiments indicate that VZV pathogenesis in skin depends upon the ORF61-mediated disruption of PML NBs and that the ORF61 SUMO-binding function is necessary for this effect. More broadly, our study elucidates the importance of PML NBs for the innate control of a viral pathogen during infection of differentiated cells within their tissue microenvironment in vivo and the requirement for a viral protein with SUMO-binding capacity to counteract this intrinsic barrier.

| S-EPMC3161977 | biostudies-literature

Network motifs: structure does not determine function.

Project description:A number of publications have recently examined the occurrence and properties of the feed-forward motif in a variety of networks, including those that are of interest in genome biology, such as gene networks. The present work looks in some detail at the dynamics of the bi-fan motif, using systems of ordinary differential equations to model the populations of transcription factors, mRNA and protein, with the aim of extending our understanding of what appear to be important building blocks of gene network structure.We develop an ordinary differential equation model of the bi-fan motif and analyse variants of the motif corresponding to its behaviour under various conditions. In particular, we examine the effects of different steady and pulsed inputs to five variants of the bifan motif, based on evidence in the literature of bifan motifs found in Saccharomyces cerevisiae (commonly known as baker's yeast). Using this model, we characterize the dynamical behaviour of the bi-fan motif for a wide range of biologically plausible parameters and configurations. We find that there is no characteristic behaviour for the motif, and with the correct choice of parameters and of internal structure, very different, indeed even opposite behaviours may be obtained.Even with this relatively simple model, the bi-fan motif can exhibit a wide range of dynamical responses. This suggests that it is difficult to gain significant insights into biological function simply by considering the connection architecture of a gene network, or its decomposition into simple structural motifs. It is necessary to supplement such structural information by kinetic parameters, or dynamic time series experimental data, both of which are currently difficult to obtain.

| S-EPMC1488845 | biostudies-other

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data