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 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.

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 Evaluation of Sequence Features from Intrinsically Disordered Regions for the Estimation of Protein Function

PLoS ONE ◽  
2014 ◽  
Vol 9 (2) ◽  
pp. e89890 ◽  
Author(s):  
Alok Sharma ◽  
Abdollah Dehzangi ◽  
James Lyons ◽  
Seiya Imoto ◽  
Satoru Miyano ◽  
...  
Keyword(s):  
Protein Function ◽  
Sequence Features ◽  
Intrinsically Disordered ◽  
Intrinsically Disordered Regions ◽  
Disordered Regions

scholarly journals The contribution of intrinsically disordered regions to protein function, cellular complexity, and human disease

2016 ◽  
Vol 44 (5) ◽  
pp. 1185-1200 ◽  
Author(s):  
M. Madan Babu
Keyword(s):  
Protein Function ◽  
Human Disease ◽  
Three Dimensional ◽  
Dimensional Structure ◽  
Sequence Structure ◽  
Intrinsically Disordered ◽  
Intrinsically Disordered Regions ◽  
The 1960S ◽  
Functional Versatility ◽  
Disordered Regions

In the 1960s, Christian Anfinsen postulated that the unique three-dimensional structure of a protein is determined by its amino acid sequence. This work laid the foundation for the sequence–structure–function paradigm, which states that the sequence of a protein determines its structure, and structure determines function. However, a class of polypeptide segments called intrinsically disordered regions does not conform to this postulate. In this review, I will first describe established and emerging ideas about how disordered regions contribute to protein function. I will then discuss molecular principles by which regulatory mechanisms, such as alternative splicing and asymmetric localization of transcripts that encode disordered regions, can increase the functional versatility of proteins. Finally, I will discuss how disordered regions contribute to human disease and the emergence of cellular complexity during organismal evolution.

scholarly journals Energetics of a protein disorder-order transition in small molecule recognition

2021 ◽  
Author(s):  
Cesar Mendoza-Martinez ◽  
Michail Papadourakis ◽  
salome llabres ◽  
Arun A Gupta ◽  
Paul N Barlow ◽  
...  
Keyword(s):  
Small Molecule ◽  
Order Transition ◽  
Protein Disorder ◽  
Enhanced Sampling ◽  
Intrinsically Disordered ◽  
Intrinsically Disordered Regions ◽  
Binding Energetics ◽  
Molecule Recognition ◽  
Dynamics Simulations ◽  
Disordered Regions

Many proteins recognise other proteins via mechanisms that involve the folding of intrinsically disordered regions upon complex formation. Here we investigate how the selectivity of a drug-like small molecule arises from its modulation of a protein disorder-to-order transition. Binding of the compound AM-7209 has been reported to confer order upon an intrinsically disordered lid region of the oncoprotein MDM2. Calorimetric measurements revealed that truncation of the lid region of MDM2 increases the dissociation constant of AM-7209 250-fold. By contrast, lid truncation has little effect on the binding of the ligand Nutlin-3a. Insights into these differential binding energetics were obtained via a complete thermodynamic analysis that featured adaptive absolute alchemical free energy of binding calculations with enhanced-sampling molecular dynamics simulations. The simulations reveal that in apo MDM2 the ordered lid state is energetically disfavoured. AM-7209, but not Nutlin-3a, shows a significant energetic preference for ordered lid conformations, thus shifting the balance towards ordering of the lid in the AM-7209/MDM2 complex. The methodology reported herein should facilitate broader targeting of intrinsically disordered regions in medicinal chemistry.

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 Tandem repeats drive variation of intrinsically disordered regions in budding yeast

2018 ◽  
Author(s):  
Michael Babokhov ◽  
Bradley I. Reinfeld ◽  
Kevin Hackbarth ◽  
Yotam Bentov ◽  
Stephen M. Fuchs
Keyword(s):  
Protein Function ◽  
Copy Number ◽  
Tandem Repeats ◽  
Budding Yeast ◽  
Amino Acid Sequences ◽  
Length Variation ◽  
Intrinsically Disordered ◽  
Intrinsically Disordered Regions ◽  
Highly Correlated ◽  
Disordered Regions

AbstractCopy-number variation in tandem repeat coding regions is more prevalent in eukaryotic genomes than current literature suggests. We have reexamined the genomes of nearly 100 yeast strains looking to map regions of repeat variation. From this analysis we have identified that length variation is highly correlated to intrinsically disordered regions (IDRs). Furthermore, the majority of length variation is associated with tandem repeats. These repetitive regions are rich in homopolymeric amino acid sequences but nearly half of the variation comes from longer-repeating motifs. Comparisons of repeat copy number and sequence between strains of budding yeast as well as closely related fungi suggest selection for and conservation of IDR-related tandem repeats. In some instances, repeat variation has been demonstrated to mediate binding affinity, aggregation, and protein stability. With this analysis, we can identify proteins for which repeat variation may play conserved roles in modulating protein function.

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