Entropy and Information within Intrinsically Disordered Protein Regions

Pritišanac, Iva; Vernon, Robert; Moses, Alan M.; Kay, Julie D. Forman

doi:10.3390/e21070662

Cited by 43 publications

(40 citation statements)

References 186 publications

(294 reference statements)

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“…We quantified conservation by measuring the mean Shannon entropy of residues constituting the N-glycosite neighborhoods and disordered regions ( Fig. 6; Supplementary File 7) [46][47][48] . Shannon entropy is a measure of the information content within a sequence.…”

Section: Scientific Reports |mentioning

confidence: 99%

Mutually exclusive locales for N-linked glycans and disorder in human glycoproteins

Goutham¹,

Kumari

Pally³

et al. 2020

Sci Rep

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Several post-translational protein modifications lie predominantly within regions of disorder: the biased localization has been proposed to expand the binding versatility of disordered regions. However, investigating a representative dataset of 500 human N-glycoproteins, we observed the sites of n-linked glycosylations or n-glycosites, to be predominantly present in the regions of predicted order. When compared with disordered stretches, ordered regions were not found to be enriched for asparagines, serines and threonines, residues that constitute the sequon signature for conjugation of N-glycans. We then investigated the basis of mutual exclusivity between disorder and N-glycosites on the basis of amino acid distribution: when compared with control ordered residue stretches without any N-glycosites, residue neighborhoods surrounding N-glycosites showed a depletion of bulky, hydrophobic and disorder-promoting amino acids and an enrichment for flexible and accessible residues that are frequently found in coiled structures. When compared with control disordered residue stretches without any N-glycosites, N-glycosite neighborhoods were depleted of charged, polar, hydrophobic and flexible residues and enriched for aromatic, accessible and order-promoting residues with a tendency to be part of coiled and β structures. N-glycosite neighborhoods also showed greater phylogenetic conservation among amniotes, compared with control ordered regions, which in turn were more conserved than disordered control regions. our results lead us to propose that unique primary structural compositions and differential propensities for evolvability allowed for the mutual spatial exclusion of n-glycosite neighborhoods and disordered stretches.One of the common co-and post-translational modifications of polypeptides is the conjugation of branched glycosylations to asparagines (known as N-linked glycosylations) 1 . N-linked glycosylation begins with the assembly of an oligosaccharide on dolichol pyrophosphate and the subsequent transfer of the oligosaccharide to the asparagine residues of polypeptides in the lumen of the endoplasmic reticulum; the oligosaccharide is further remodeled in the Golgi complex. Several proteins that end up in the extracellular milieu or as transmembrane proteins are N-linked glycoconjugates. The establishment of organismal morphologies has been sought to be understood through the interactions of a highly conserved set of proteins known as the developmental genetic toolkit 2 . Most toolkit proteins, which are involved in tissue-scale processes, such as cell-cell and cell-matrix adhesion, diffusion-driven signaling and cell movement, are extracellular-or membrane-bound glycoproteins 3,4 . The fundamental role of such toolkit proteins in mechanisms of organ-and organismal-development across diverse clades suggests evolutionary constraints on their structures and folds, while they may have continued to evolve to perform newer functions as organisms occupied and constructed newer niches.A large number of eukaryotic pro...

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Section: Scientific Reports |mentioning

confidence: 99%

Mutually exclusive locales for N-linked glycans and disorder in human glycoproteins

Goutham¹,

Kumari

Pally³

et al. 2020

Sci Rep

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“…Since there is typically a low sequence homology in related IDPs, we postulate that the conservation of (aro-Pro) sequence patterns indicates the existence of relevant and specific aro-Pro interactions and therefore suggests the existence of compact segments. It will be interesting to see whether this information can be used as a primarysequence search criterion to identify IDPs with distinct structural properties, as proposed elsewhere [84].…”

Section: Discussionmentioning

confidence: 99%

The Ambivalent Role of Proline Residues in an Intrinsically Disordered Protein: From Disorder Promoters to Compaction Facilitators

Mateos

Conrad-Billroth

Schiavina

et al. 2020

Journal of Molecular Biology

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Intrinsically disordered proteins (IDPs) carry out many biological functions. They lack a stable three-dimensional structure, but rather adopt many different conformations in dynamic equilibrium. The interplay between local dynamics and global rearrangements is key for their function. In IDPs, proline residues are significantly enriched. Given their unique physicochemical and structural properties, a more detailed understanding of their potential role in stabilizing partially folded states in IDPs is highly desirable. Nuclear magnetic resonance (NMR) spectroscopy, and in particular 13 C-detected NMR, is especially suitable to address these questions. We applied a 13 C-detected strategy to study Osteopontin, a largely disordered IDP with a central compact region. By employing the exquisite sensitivity and spectral resolution of these novel techniques we gained unprecedented insight into cis-Pro populations, their local structural dynamics and their role in mediating long-range contacts. Our findings clearly call for a reassessment of the structural and functional role of proline residues in IDPs. The emerging picture shows that proline residues have ambivalent structural roles. They are not simply disorder promoters but rather can, depending on the primary sequence context, act as nucleation sites for structural compaction in IDPs. These unexpected features provide a versatile mechanistic toolbox to enrich the conformational ensembles of IDPs with specific features for adapting to changing molecular and cellular environments.

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“…The significance of this SLiM is indicated by its evolutionary conservation ( Fig. 1), despite its occurrence in an IDR where frequently positional conservation is not observed (67,68). We used CPMG RD (Fig.…”

Section: Discussionmentioning

confidence: 99%

Dysregulated interactions triggered by a neuropathy-causing mutation in the IPV motif of HSP27

Alderson

Adriaenssens

Asselbergh

et al. 2019

Preprint

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Molecular chaperone | small heat-shock protein | Charcot-Marie-Tooth disease | short linear motif | nuclear magnetic resonance | protein aggregation | neurological diseaseCorrespondence: vincent.timmerman@uantwerpen.be, andrew.baldwin@chem.ox.ac.uk, justin.benesch@chem.ox.ac.uk the backbone atoms of V111, T113, and L157 (Fig. 1E). In HSP27, the IxI/V motif corresponds to I181-P182-V183; the Ile and Val residues penetrate the β4/β8 groove while P182 does not make any direct contacts with the ACD (Fig. 1E).The P182L variant has impaired chaperone activity in vitro. We purified recombinant human HSP27 and the CMTimplicated P182L variant from E. coli, and compared their chaperone activities in vitro using a substrate aggregation assay. We tested their ability to prevent the aggregation of two model substrate proteins, malate dehydrogenase (MDH) and

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Entropy and Information within Intrinsically Disordered Protein Regions

Cited by 43 publications

References 186 publications

Mutually exclusive locales for N-linked glycans and disorder in human glycoproteins

Mutually exclusive locales for N-linked glycans and disorder in human glycoproteins

The Ambivalent Role of Proline Residues in an Intrinsically Disordered Protein: From Disorder Promoters to Compaction Facilitators

Dysregulated interactions triggered by a neuropathy-causing mutation in the IPV motif of HSP27

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