scholarly journals Structural propensity database of proteins

2017 ◽  
Author(s):  
Kamil Tamiola ◽  
Matthew M Heberling ◽  
Jan Domanski
Keyword(s):  
Structural Dynamics ◽  
Protein Function ◽  
Chemical Shifts ◽  
Protein Disorder ◽  
Computational Biophysics ◽  
Intrinsic Protein ◽  
Intrinsically Disordered ◽  
Intrinsically Disordered Regions ◽  
Intrinsic Protein Disorder ◽  
Structural Insights

AbstractAn overwhelming amount of experimental evidence suggests that elucidations of protein function, interactions, and pathology are incomplete without inclusion of intrinsic protein disorder and structural dynamics. Thus, to expand our understanding of intrinsic protein disorder, we have created a database of secondary structure (SS) propensities for proteins (dSPP) as a reference resource for experimental research and computational biophysics. The dSPP comprises SS propensities of 7,094 unrelated proteins, as gauged from NMR chemical shift measurements in solution and solid state. Here, we explain the concept of SS propensity and analyze dSPP entries of therapeutic relevance, α-synuclein, MOAG-4, and the ZIKA NS2B-NS3 complex to show: (1) how propensity mapping generates novel structural insights into intrinsically disordered regions of pathologically relevant proteins, (2) how computational biophysics tools can benefit from propensity mapping, and (3) how the residual disorder estimation based on NMR chemical shifts compares with sequence-based disorder predictors. This work demonstrates the benefit of propensity estimation as a method that reports both on protein structure, lability, and disorder.

scholarly journals Ubiquitin Interacting Motifs: Duality Between Structured and Disordered Motifs

2021 ◽  
Vol 8 ◽  
Author(s):  
Matteo Lambrughi ◽  
Emiliano Maiani ◽  
Burcu Aykac Fas ◽  
Gary S. Shaw ◽  
Birthe B. Kragelund ◽  
...  
Keyword(s):  
Protein Function ◽  
Chemical Shifts ◽  
Helical Structures ◽  
Conserved Sequence ◽  
Intrinsically Disordered ◽  
Intrinsically Disordered Regions ◽  
Multiple Partners ◽  
Common Motif ◽  
Dynamics Simulations ◽  
Disordered Regions

Ubiquitin is a small protein at the heart of many cellular processes, and several different protein domains are known to recognize and bind ubiquitin. A common motif for interaction with ubiquitin is the Ubiquitin Interacting Motif (UIM), characterized by a conserved sequence signature and often found in multi-domain proteins. Multi-domain proteins with intrinsically disordered regions mediate interactions with multiple partners, orchestrating diverse pathways. Short linear motifs for binding are often embedded in these disordered regions and play crucial roles in modulating protein function. In this work, we investigated the structural propensities of UIMs using molecular dynamics simulations and NMR chemical shifts. Despite the structural portrait depicted by X-crystallography of stable helical structures, we show that UIMs feature both helical and intrinsically disordered conformations. Our results shed light on a new class of disordered UIMs. This group is here exemplified by the C-terminal domain of one isoform of ataxin-3 and a group of ubiquitin-specific proteases. Intriguingly, UIMs not only bind ubiquitin. They can be a recruitment point for other interactors, such as parkin and the heat shock protein Hsc70-4. Disordered UIMs can provide versatility and new functions to the client proteins, opening new directions for research on their interactome.

scholarly journals Association between intrinsic disorder and serine/threonine phosphorylation in Mycobacterium tuberculosis

2014 ◽  
Author(s):  
Gajinder P Singh
Keyword(s):  
Protein Function ◽  
Substrate Recognition ◽  
Intrinsic Disorder ◽  
Protein Disorder ◽  
Phosphorylation Sites ◽  
Recognition Mechanism ◽  
Intrinsically Disordered ◽  
Intrinsically Disordered Regions ◽  
Regulate Protein ◽  
Disordered Regions

Serine/threonine phosphorylation is an important mechanism to regulate protein function. In eukaryotes phosphorylation occurs predominantly in intrinsically disordered regions of proteins. While serine/threonine phosphorylation and protein disorder are much less prevalent in prokaryotes, M. tuberculosis has both high serine/threonine phosphorylation and disorder. Here I show that, similar to eukaryotes, serine/threonine phosphorylation sites in M. tuberculosis are highly enriched in intrinsically disordered regions, indicating similarity in substrate recognition mechanism of eukaryotic and M. tuberculosis kinases. Serine/threonine phosphorylation has been linked to the pathogenicity and survival of M. tuberculosis, thus better understanding of how its kinases recognize their substrates could have important implications in understanding and controlling the biology of this deadly pathogen.

scholarly journals Association between intrinsic disorder and serine/threonine phosphorylation in Mycobacterium tuberculosis

2014 ◽  
Author(s):  
Gajinder P Singh
Keyword(s):  
Protein Function ◽  
Substrate Recognition ◽  
Intrinsic Disorder ◽  
Protein Disorder ◽  
Phosphorylation Sites ◽  
Recognition Mechanism ◽  
Intrinsically Disordered ◽  
Intrinsically Disordered Regions ◽  
Regulate Protein ◽  
Disordered Regions

Serine/threonine phosphorylation is an important mechanism to regulate protein function. In eukaryotes phosphorylation occurs predominantly in intrinsically disordered regions of proteins. While serine/threonine phosphorylation and protein disorder are much less prevalent in prokaryotes, M. tuberculosis has both high serine/threonine phosphorylation and disorder. Here I show that, similar to eukaryotes, serine/threonine phosphorylation sites in M. tuberculosis are highly enriched in intrinsically disordered regions, indicating similarity in substrate recognition mechanism of eukaryotic and M. tuberculosis kinases. Serine/threonine phosphorylation has been linked to the pathogenicity and survival of M. tuberculosis, thus better understanding of how its kinases recognize their substrates could have important implications in understanding and controlling the biology of this deadly pathogen.

scholarly journals Embeddings from deep learning transfer GO annotations beyond homology

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Maria Littmann ◽  
Michael Heinzinger ◽  
Christian Dallago ◽  
Tobias Olenyi ◽  
Burkhard Rost
Keyword(s):  
Protein Function ◽  
Protein Sequences ◽  
Language Models ◽  
Evolutionary Information ◽  
Pairwise Sequence Identity ◽  
Intrinsically Disordered ◽  
Intrinsically Disordered Regions ◽  
Sequence Identity ◽  
Experimental Function ◽  
Go Terms

AbstractKnowing protein function is crucial to advance molecular and medical biology, yet experimental function annotations through the Gene Ontology (GO) exist for fewer than 0.5% of all known proteins. Computational methods bridge this sequence-annotation gap typically through homology-based annotation transfer by identifying sequence-similar proteins with known function or through prediction methods using evolutionary information. Here, we propose predicting GO terms through annotation transfer based on proximity of proteins in the SeqVec embedding rather than in sequence space. These embeddings originate from deep learned language models (LMs) for protein sequences (SeqVec) transferring the knowledge gained from predicting the next amino acid in 33 million protein sequences. Replicating the conditions of CAFA3, our method reaches an Fmax of 37 ± 2%, 50 ± 3%, and 57 ± 2% for BPO, MFO, and CCO, respectively. Numerically, this appears close to the top ten CAFA3 methods. When restricting the annotation transfer to proteins with < 20% pairwise sequence identity to the query, performance drops (Fmax BPO 33 ± 2%, MFO 43 ± 3%, CCO 53 ± 2%); this still outperforms naïve sequence-based transfer. Preliminary results from CAFA4 appear to confirm these findings. Overall, this new concept is likely to change the annotation of proteins, in particular for proteins from smaller families or proteins with intrinsically disordered regions.

scholarly journals Origins of Myc Proteins – Using Intrinsic Protein Disorder to Trace Distant Relatives

PLoS ONE ◽  
2013 ◽  
Vol 8 (9) ◽  
pp. e75057 ◽  
Author(s):  
Amir Mahani ◽  
Johan Henriksson ◽  
Anthony P. H. Wright
Keyword(s):  
Protein Disorder ◽  
Intrinsic Protein ◽  
Intrinsic Protein Disorder

scholarly journals Random coil chemical shifts for serine, threonine and tyrosine phosphorylation over a broad pH range

2019 ◽  
Vol 73 (12) ◽  
pp. 713-725 ◽  
Author(s):  
Ruth Hendus-Altenburger ◽  
Catarina B. Fernandes ◽  
Katrine Bugge ◽  
Micha B. A. Kunze ◽  
Wouter Boomsma ◽  
...  
Keyword(s):  
Chemical Shift ◽  
Secondary Structure ◽  
Intrinsically Disordered Proteins ◽  
Chemical Shifts ◽  
Random Coil ◽  
Disordered Proteins ◽  
Phosphoryl Group ◽  
Intrinsically Disordered ◽  
Intrinsically Disordered Regions ◽  
Secondary Chemical

Abstract Phosphorylation is one of the main regulators of cellular signaling typically occurring in flexible parts of folded proteins and in intrinsically disordered regions. It can have distinct effects on the chemical environment as well as on the structural properties near the modification site. Secondary chemical shift analysis is the main NMR method for detection of transiently formed secondary structure in intrinsically disordered proteins (IDPs) and the reliability of the analysis depends on an appropriate choice of random coil model. Random coil chemical shifts and sequence correction factors were previously determined for an Ac-QQXQQ-NH2-peptide series with X being any of the 20 common amino acids. However, a matching dataset on the phosphorylated states has so far only been incompletely determined or determined only at a single pH value. Here we extend the database by the addition of the random coil chemical shifts of the phosphorylated states of serine, threonine and tyrosine measured over a range of pH values covering the pKas of the phosphates and at several temperatures (www.bio.ku.dk/sbinlab/randomcoil). The combined results allow for accurate random coil chemical shift determination of phosphorylated regions at any pH and temperature, minimizing systematic biases of the secondary chemical shifts. Comparison of chemical shifts using random coil sets with and without inclusion of the phosphoryl group, revealed under/over estimations of helicity of up to 33%. The expanded set of random coil values will improve the reliability in detection and quantification of transient secondary structure in phosphorylation-modified IDPs.

scholarly journals Towards an understanding of the role of intrinsic protein disorder on plant adaptation to environmental challenges

2020 ◽  
Vol 26 (1) ◽  
pp. 141-150 ◽  
Author(s):  
Jesús Alejandro Zamora-Briseño ◽  
Alejandro Pereira-Santana ◽  
Sandi Julissa Reyes-Hernández ◽  
Daniel Cerqueda-García ◽  
Enrique Castaño ◽  
...  
Keyword(s):  
Protein Disorder ◽  
Plant Adaptation ◽  
Environmental Challenges ◽  
Intrinsic Protein ◽  
Intrinsic Protein Disorder

scholarly journals Intrinsically disordered regions are abundant in simplexvirus proteomes and display signatures of positive selection

2020 ◽  
Vol 6 (1) ◽  
Author(s):  
Alessandra Mozzi ◽  
Diego Forni ◽  
Rachele Cagliani ◽  
Mario Clerici ◽  
Uberto Pozzoli ◽  
...  
Keyword(s):  
Positive Selection ◽  
Protein Function ◽  
Three Dimensional ◽  
New Host ◽  
Intrinsically Disordered ◽  
Intrinsically Disordered Regions ◽  
Human Proteins ◽  
Simplex Virus ◽  
Herpes Simplex Virus 2 ◽  
Disordered Regions

Abstract Whereas the majority of herpesviruses co-speciated with their mammalian hosts, human herpes simplex virus 2 (HSV-2, genus Simplexvirus) most likely originated from the cross-species transmission of chimpanzee herpesvirus 1 to an ancestor of modern humans. We exploited the peculiar evolutionary history of HSV-2 to investigate the selective events that drove herpesvirus adaptation to a new host. We show that HSV-2 intrinsically disordered regions (IDRs)—that is, protein domains that do not adopt compact three-dimensional structures—are strongly enriched in positive selection signals. Analysis of viral proteomes indicated that a significantly higher portion of simplexvirus proteins is disordered compared with the proteins of other human herpesviruses. IDR abundance in simplexvirus proteomes was not a consequence of the base composition of their genomes (high G + C content). Conversely, protein function determines the IDR fraction, which is significantly higher in viral proteins that interact with human factors. We also found that the average extent of disorder in herpesvirus proteins tends to parallel that of their human interactors. These data suggest that viruses that interact with fast-evolving, disordered human proteins, in turn, evolve disordered viral interactors poised for innovation. We propose that the high IDR fraction present in simplexvirus proteomes contributes to their wider host range compared with other herpesviruses.

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