Direct prediction of intrinsically disordered protein conformational properties from sequence

Lotthammer, Jeffrey M.; Ginell, Garrett M.; Griffith, Daniel; Emenecker, Ryan J.; Holehouse, Alex S.

doi:10.1038/s41592-023-02159-5

Cited by 34 publications

(23 citation statements)

References 107 publications

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“…Another 15% of the total (27/177) were observed in both female gametocytes and zygotes. These qualitative data are consistent with a phosphorylation-based regulation of the members of this complex, such as on the positionally conserved Ser20 of DOZI within a predicted intrinsically disordered region in its N-terminus (76). While these findings coincide with the release of its translationally repressive activity, establishing whether and which modifications are causal remains to be determined.…”

Section: Resultssupporting

confidence: 81%

Global Release of Translational Repression AcrossPlasmodium’sHost-to-Vector Transmission Event

Rios,

McGee,

Sebastian

et al. 2024

Preprint

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Malaria parasites must be able to respond quickly to changes in their environment, including during their transmission between mammalian hosts and mosquito vectors. Therefore, before transmission, female gametocytes proactively produce and translationally repress mRNAs that encode essential proteins that the zygote requires to establish a new infection. This essential regulatory control requires the orthologues of DDX6 (DOZI), LSM14a (CITH), and ALBA proteins to form a translationally repressive complex in female gametocytes that associates with many of the affected mRNAs. However, while the release of translational repression of individual mRNAs has been documented, the details of the global release of translational repression have not. Moreover, the changes in spatial arrangement and composition of the DOZI/CITH/ALBA complex that contribute to translational control are also not known.Therefore, we have conducted the first quantitative, comparative transcriptomics and DIA-MS proteomics ofPlasmodiumparasites across the host-to-vector transmission event to document the global release of translational repression. Using female gametocytes and zygotes ofP. yoelii, we found that nearly 200 transcripts are released for translation soon after fertilization, including those with essential functions for the zygote. However, we also observed that some transcripts remain repressed beyond this point. In addition, we have used TurboID-based proximity proteomics to interrogate the spatial and compositional changes in the DOZI/CITH/ALBA complex across this transmission event. Consistent with recent models of translational control, proteins that associate with either the 5’ or 3’ end of mRNAs are in close proximity to one another during translational repression in female gametocytes and then dissociate upon release of repression in zygotes. This observation is cross-validated for several protein colocalizations in female gametocytes via ultrastructure expansion microscopy and structured illumination microscopy. Moreover, DOZI exchanges its interaction from NOT1-G in female gametocytes to the canonical NOT1 in zygotes, providing a model for a trigger for the release of mRNAs from DOZI. Finally, unenriched phosphoproteomics revealed the modification of key translational control proteins in the zygote. Together, these data provide a model for the essential translational control mechanisms used by malaria parasites to promote their efficient transmission from their mammalian host to their mosquito vector.

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Section: Resultssupporting

confidence: 81%

Global Release of Translational Repression AcrossPlasmodium’sHost-to-Vector Transmission Event

Rios,

McGee,

Sebastian

et al. 2024

Preprint

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“…Our next step could be to study the aggregate properties of IDRs in the psychiatric disease-related proteins, including radius of gyration, end-to-end distance, polymer scaling index, and aggregate a sphericity. We might also explore the impact of conformational changes of IDRs in mental diseaseassociated proteins on the function of full-length proteins and how conformational changes of IDRs in mental diseases are linked to cellular function, localization, amino acid sequences, evolutionary conservation, and disease variation, in conjunction with another newly released molecular model for generating IDR conformational assemblies [67,68].We hope that our research will advance a deeper understanding of the pathogenic mechanisms of psychiatric disorders, and offer new insights for future diagnosis and treatment.…”

Section: Discussionmentioning

confidence: 99%

Landscape of Intrinsically Disordered Proteins in Mental Disorder Diseases

Zhang,

Yang,

et al. 2024

Preprint

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Intrinsically Disordered Proteins (IDPs) play crucial roles in signal transduction, cell differentiation, and transcriptional regulation. Many disrupted genes associated with mental disorders are identified as IDPs, and emerging evidence suggests the functional role of IDPs in neuropsychiatric disorders. However, few studies comprehensively explore the functional association between protein disorder properties and different mental diseases. To address this gap, we collected disrupted gene sets for seven mental diseases (MDD, SCZ, BP, ID, AD, ADHD, ASD) and a control gene set from normal brains using DisGeNET and GeneCards databases. The state-of-the-art predictor IUPred2A was then utilized to calculate the disorder properties , followed by a thorough comparison between the disordered proteins in mental diseases and healthy controls. Functional enrichment analysis and protein-protein interaction networks were conducted to investigate the IDPs’ functional roles in psychiatric diseases. Additionally, we demonstrated the role of IDPs in protein binding formations through a case study of alpha-synuclein using protein docking. Our findings reveal that differentially expressed proteins in mental disorders, especially in ASD and ADHD, exhibit more IDPs than those in healthy controls. IDPs in psychiatric disorders are significantly enriched in neurodevelopmental pathways and play an important role in in gene expression regulation. Our results indicate distinct functional patterns of disorder proteins among mental diseases and healthy controls. When comparing the IDPs between ASD and ADHD, we observed that IDPs in ADHD are more likely linked to the synaptic signaling and regulation, while IDPs in ASD are more tendentiously related to diverse and complex biological processes. Our work offers valuable insights into the important functions of IDPs in psychiatric disorders, enhancing our understanding of the molecular mechanisms involved in psychiatric disorders.

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“…Furthermore, proteomics would enable us to improve our current, but so far still rather scant, knowledge of their binding promiscuity. Ultimately, based on the existing scientific community projects (i.e., ELIXIR) [66], as well as on the freshly developed deep-and machine-learning approaches [67], the prediction of IDRs should be greatly facilitated and boosted.…”

Section: Outlook and Outstanding Questionsmentioning

confidence: 99%

Never Fold to Fold Continuously: A Conundrum in Ubiquitin–Proteasome System (UPS)-Mediated Protein Quality Control (PQC)

Magnati,

Bracco

2024

Biophysica

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In the last few decades, the traditional paradigm of teleonomy, in which the amino acid sequence of a protein is tightly associated with its structure and, in turn, with its function, has been partially undermined. The idea of a protein as a two-state object has been superseded by that of understanding it as a multistate object. Indeed, some proteins, or portions of a protein, display intrinsically disordered regions (IDRs), which means that they lack stable secondary or tertiary structures. While we are aware that IDRs are present in almost half of the total human proteins, we are still quite far away from understanding their contextual-specific functions and figuring out how they mechanistically work. In the present perspective article, we will attempt to summarize the role/s of IDRs in ubiquitin–proteasome system (UPS)-mediated protein quality control (PQC) at different levels, ranging from ubiquitination to protein degradation through the proteasome machinery up to their role in decoding the complex ubiquitin code. Ultimately, we will critically discuss the future challenges we are facing to gain insights into the role of IDRs in regulating UPS-mediated PQC.

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Direct prediction of intrinsically disordered protein conformational properties from sequence

Cited by 34 publications

References 107 publications

Global Release of Translational Repression AcrossPlasmodium’sHost-to-Vector Transmission Event

Global Release of Translational Repression AcrossPlasmodium’sHost-to-Vector Transmission Event

Landscape of Intrinsically Disordered Proteins in Mental Disorder Diseases

Never Fold to Fold Continuously: A Conundrum in Ubiquitin–Proteasome System (UPS)-Mediated Protein Quality Control (PQC)

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