scholarly journals KMAD: knowledge-based multiple sequence alignment for intrinsically disordered proteins

2015 ◽  
Vol 32 (6) ◽  
pp. 932-936 ◽  
Author(s):  
Joanna Lange ◽  
Lucjan S. Wyrwicz ◽  
Gert Vriend
Keyword(s):  
Sequence Alignment ◽  
Multiple Sequence Alignment ◽  
Active Sites ◽  
Intrinsically Disordered Proteins ◽  
Tertiary Structure ◽  
Substitution Matrix ◽  
Disordered Proteins ◽  
Multiple Sequence ◽  
Intrinsically Disordered ◽  
Knowledge Based

Abstract Summary: Intrinsically disordered proteins (IDPs) lack tertiary structure and thus differ from globular proteins in terms of their sequence–structure–function relations. IDPs have lower sequence conservation, different types of active sites and a different distribution of functionally important regions, which altogether make their multiple sequence alignment (MSA) difficult. The KMAD MSA software has been written specifically for the alignment and annotation of IDPs. It augments the substitution matrix with knowledge about post-translational modifications, functional domains and short linear motifs. Results: MSAs produced with KMAD describe well-conserved features among IDPs, tend to agree well with biological intuition, and are a good basis for designing new experiments to shed light on this large, understudied class of proteins. Availability and implementation: KMAD web server is accessible at http://www.cmbi.ru.nl/kmad/. A standalone version is freely available. Contact: [email protected]

scholarly journals Genetically tunable frustration controls allostery in an intrinsically disordered transcription factor

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Jing Li ◽  
Jordan T White ◽  
Harry Saavedra ◽  
James O Wrabl ◽  
Hesam N Motlagh ◽  
...  
Keyword(s):  
Transcriptional Activation ◽  
Structural Changes ◽  
Intrinsically Disordered Proteins ◽  
Tertiary Structure ◽  
Control Function ◽  
Disordered Proteins ◽  
Intrinsically Disordered ◽  
Novel Strategy ◽  
Structured Proteins

Intrinsically disordered proteins (IDPs) present a functional paradox because they lack stable tertiary structure, but nonetheless play a central role in signaling, utilizing a process known as allostery. Historically, allostery in structured proteins has been interpreted in terms of propagated structural changes that are induced by effector binding. Thus, it is not clear how IDPs, lacking such well-defined structures, can allosterically affect function. Here, we show a mechanism by which an IDP can allosterically control function by simultaneously tuning transcriptional activation and repression, using a novel strategy that relies on the principle of ‘energetic frustration’. We demonstrate that human glucocorticoid receptor tunes this signaling in vivo by producing translational isoforms differing only in the length of the disordered region, which modulates the degree of frustration. We expect this frustration-based model of allostery will prove to be generally important in explaining signaling in other IDPs.

scholarly journals CopulaNet: Learning residue co-evolution directly from multiple sequence alignment for protein structure prediction

2020 ◽  
Author(s):  
Fusong Ju ◽  
Jianwei Zhu ◽  
Bin Shao ◽  
Lupeng Kong ◽  
Tie-Yan Liu ◽  
...  
Keyword(s):  
Protein Structure ◽  
Protein Structure Prediction ◽  
Sequence Alignment ◽  
Multiple Sequence Alignment ◽  
Structure Prediction ◽  
Tertiary Structure ◽  
Query Protein ◽  
Spatial Proximity ◽  
Multiple Sequence ◽  
Variance Matrix

Protein functions are largely determined by the final details of their tertiary structures, and the structures could be accurately reconstructed based on inter-residue distances. Residue co-evolution has become the primary principle for estimating inter-residue distances since the residues in close spatial proximity tend to co-evolve. The widely-used approaches infer residue co-evolution using an indirect strategy, i.e., they first extract from the multiple sequence alignment (MSA) of query protein some handcrafted features, say, co-variance matrix, and then infer residue co-evolution using these features rather than the raw information carried by MSA. This indirect strategy always leads to considerable information loss and inaccurate estimation of inter-residue distances. Here, we report a deep neural network framework (called CopulaNet) to learn residue co-evolution directly from MSA without any handcrafted features. The CopulaNet consists of two key elements: i) an encoder to model context-specific mutation for each residue, and ii) an aggregator to model correlations among residues and thereafter infer residue co-evolutions. Using the CASP13 (the 13th Critical Assessment of Protein Structure Prediction) target proteins as representatives, we demonstrated the successful application of CopulaNet for estimating inter-residue distances and further predicting protein tertiary structure with improved accuracy and efficiency. Head-to-head comparison suggested that for 24 out of the 31 free modeling CASP13 domains, ProFOLD outperformed AlphaFold, one of the state-of-the-art prediction approaches.

scholarly journals Sequence specificity despite intrinsic disorder: how a disease-associated Val/Met polymorphism rearranges tertiary interactions in a long disordered protein

2019 ◽  
Author(s):  
Ruchi Lohia ◽  
Reza Salari ◽  
Grace Brannigan
Keyword(s):  
Electrostatic Interactions ◽  
Intrinsically Disordered Proteins ◽  
Tertiary Structure ◽  
Protein A ◽  
Md Simulations ◽  
Disordered Proteins ◽  
Sequence Specificity ◽  
Intrinsically Disordered ◽  
Specific Effects ◽  
Non Local

<p>The role of electrostatic interactions and mutations that change charge states in intrinsically disordered proteins (IDPs) is well-established, but many disease-associated mutations in IDPs are charge-neutral. The Val66Met single nucleotide polymorphism (SNP) in precursor brain-derived neurotrophic factor (BDNF) is one of the earliest SNPs to be associated with neuropsychiatric disorders, and the underlying molecular mechanism is unknown. Here we report on over 250 μs of fully-atomistic, explicit solvent, temperature replica exchange molecular dynamics (MD) simulations of the 91 residue BDNF prodomain, for both the V66 and M66 sequence. The simulations were able to correctly reproduce the location of both local and non-local secondary changes due to the Val66Met mutation when compared with NMR spectroscopy. We find that the change in local structure is mediated via entropic and sequence specific effects. We developed a hierarchical sequence-based framework for analysis and conceptualization, which first identifies “blobs” of 5-15 residues representing local globular regions or linkers. We use this framework within a novel test for enrichment of higher-order (tertiary) structure in disordered proteins; the size and shape of each blob is extracted from MD simulation of the real protein (RP), and used to parameterize a self-avoiding heterogenous polymer (SAHP). The SAHP version of the BDNF prodomain suggested a protein segmented into three regions, with a central long, highly disordered polyampholyte linker separating two globular regions. This effective segmentation was also observed in full simulations of the RP, but the Val66Met substitution significantly increased interactions across the linker, as well as the number of participating residues. The Val66Met substitution replaces β-bridging between Val66 and Val94 (on either side of the linker) with specific side-chain interactions between Met66 and Met95.The protein backbone in the vicinity of Met95 is then free to form β-bridges with residues 31-41 near the N-terminus, which condenses the protein. A significant role for Met/Met interactions is consistent with previously-observed non-local effects of the Val66Met SNP, as well as established interactions between the Met66 sequence and a Met-rich receptor that initiates neuronal growth cone retraction.</p>

scholarly journals The mechanism of coupled folding-upon-binding of an intrinsically disordered protein

2020 ◽  
Author(s):  
Paul Robustelli ◽  
Stefano Piana ◽  
David E. Shaw
Keyword(s):  
Measles Virus ◽  
Intrinsically Disordered Proteins ◽  
Tertiary Structure ◽  
Disordered Proteins ◽  
Binding Process ◽  
Intrinsically Disordered ◽  
Disordered Protein ◽  
Induced Folding ◽  
Helical Content ◽  
Intermolecular Contacts

AbstractIntrinsically disordered proteins (IDPs), which in isolation do not adopt a well-defined tertiary structure but instead populate a structurally heterogeneous ensemble of interconverting states, play important roles in many biological pathways. IDPs often fold into ordered states upon binding to their physiological interaction partners (a so-called “folding-upon-binding” process), but it has proven difficult to obtain an atomic-level description of the structural mechanisms by which they do so. Here, we describe in atomic detail the folding-upon-binding mechanism of an IDP segment to its binding partner, as observed in unbiased molecular dynamics simulations. In our simulations, we observed over 70 binding and unbinding events between the α-helical molecular recognition element (α-MoRE) of the intrinsically disordered C-terminal domain of the measles virus nucleoprotein (NTAIL) and the X domain (XD) of the measles virus phosphoprotein complex. We found that folding-upon-binding primarily occurred through induced-folding pathways (in which intermolecular contacts form before or concurrently with the secondary structure of the disordered protein)—an observation supported by previous experiments—and that the transition state ensemble was characterized by the formation of just a few key intermolecular contacts, and was otherwise highly structurally heterogeneous. We found that when a large amount of helical content was present early in a transition path, NTAIL typically unfolded, then refolded after additional intermolecular contacts formed. We also found that, among conformations with similar numbers of intermolecular contacts, those with less helical content had a higher probability of ultimately forming the native complex than conformations with more helical content, which were more likely to unbind. These observations suggest that even after intermolecular contacts have formed, disordered regions can have a kinetic advantage over folded regions in the folding-upon-binding process.

scholarly journals Sequence specificity despite intrinsic disorder: how a disease-associated Val/Met polymorphism rearranges tertiary interactions in a long disordered protein

2019 ◽  
Author(s):  
Ruchi Lohia ◽  
Reza Salari ◽  
Grace Brannigan
Keyword(s):  
Electrostatic Interactions ◽  
Intrinsically Disordered Proteins ◽  
Tertiary Structure ◽  
Protein A ◽  
Md Simulations ◽  
Disordered Proteins ◽  
Sequence Specificity ◽  
Intrinsically Disordered ◽  
Specific Effects ◽  
Non Local

<p>The role of electrostatic interactions and mutations that change charge states in intrinsically disordered proteins (IDPs) is well-established, but many disease-associated mutations in IDPs are charge-neutral. The Val66Met single nucleotide polymorphism (SNP) in precursor brain-derived neurotrophic factor (BDNF) is one of the earliest SNPs to be associated with neuropsychiatric disorders, and the underlying molecular mechanism is unknown. Here we report on over 250 μs of fully-atomistic, explicit solvent, temperature replica exchange molecular dynamics (MD) simulations of the 91 residue BDNF prodomain, for both the V66 and M66 sequence. The simulations were able to correctly reproduce the location of both local and non-local secondary changes due to the Val66Met mutation when compared with NMR spectroscopy. We find that the change in local structure is mediated via entropic and sequence specific effects. We developed a hierarchical sequence-based framework for analysis and conceptualization, which first identifies “blobs” of 5-15 residues representing local globular regions or linkers. We use this framework within a novel test for enrichment of higher-order (tertiary) structure in disordered proteins; the size and shape of each blob is extracted from MD simulation of the real protein (RP), and used to parameterize a self-avoiding heterogenous polymer (SAHP). The SAHP version of the BDNF prodomain suggested a protein segmented into three regions, with a central long, highly disordered polyampholyte linker separating two globular regions. This effective segmentation was also observed in full simulations of the RP, but the Val66Met substitution significantly increased interactions across the linker, as well as the number of participating residues. The Val66Met substitution replaces β-bridging between Val66 and Val94 (on either side of the linker) with specific side-chain interactions between Met66 and Met95.The protein backbone in the vicinity of Met95 is then free to form β-bridges with residues 31-41 near the N-terminus, which condenses the protein. A significant role for Met/Met interactions is consistent with previously-observed non-local effects of the Val66Met SNP, as well as established interactions between the Met66 sequence and a Met-rich receptor that initiates neuronal growth cone retraction.</p>

About TFE: Old and New Findings

2019 ◽  
Vol 20 (5) ◽  
pp. 425-451 ◽  
Author(s):  
Marian Vincenzi ◽  
Flavia A. Mercurio ◽  
Marilisa Leone
Keyword(s):  
Secondary Structure ◽  
Intrinsically Disordered Proteins ◽  
Tertiary Structure ◽  
Disordered Proteins ◽  
Helical Conformation ◽  
Specific Amino Acid ◽  
Molecular Systems ◽  
Intrinsically Disordered ◽  
New Findings ◽  
Fluorinated Alcohol

The fluorinated alcohol 2,2,2-Trifluoroethanol (TFE) has been implemented for many decades now in conformational studies of proteins and peptides. In peptides, which are often disordered in aqueous solutions, TFE acts as secondary structure stabilizer and primarily induces an &#945; -helical conformation. The exact mechanism through which TFE plays its stabilizing roles is still debated and direct and indirect routes, relying either on straight interaction between TFE and molecules or indirect pathways based on perturbation of solvation sphere, have been proposed. Another still unanswered question is the capacity of TFE to favor in peptides a bioactive or a native-like conformation rather than simply stimulate the raise of secondary structure elements that reflect only the inherent propensity of a specific amino-acid sequence. In protein studies, TFE destroys unique protein tertiary structure and often leads to the formation of non-native secondary structure elements, but, interestingly, gives some hints about early folding intermediates. In this review, we will summarize proposed mechanisms of TFE actions. We will also describe several examples, in which TFE has been successfully used to reveal structural properties of different molecular systems, including antimicrobial and aggregation-prone peptides, as well as globular folded and intrinsically disordered proteins.

scholarly journals AlexSys: a knowledge-based expert system for multiple sequence alignment construction and analysis

2010 ◽  
Vol 38 (19) ◽  
pp. 6338-6349 ◽  
Author(s):  
M. R. Aniba ◽  
O. Poch ◽  
A. Marchler-Bauer ◽  
J. D. Thompson
Keyword(s):  
Expert System ◽  
Sequence Alignment ◽  
Multiple Sequence Alignment ◽  
Multiple Sequence ◽  
Knowledge Based

Disorder-function relationships for the cell cycle regulatory proteins p21 and p27

2012 ◽  
Vol 393 (4) ◽  
pp. 259-274 ◽  
Author(s):  
Diana M. Mitrea ◽  
Mi-Kyung Yoon ◽  
Li Ou ◽  
Richard W. Kriwacki
Keyword(s):  
Cell Division ◽  
Molecular Mechanisms ◽  
Intrinsically Disordered Proteins ◽  
Tertiary Structure ◽  
Structural Features ◽  
Disordered Proteins ◽  
Cellular Functions ◽  
Intrinsically Disordered ◽  
Induced Folding ◽  
Cell Cycle Regulatory Proteins

Abstract The classic structure-function paradigm has been challenged by a recently identified class of proteins: intrinsically disordered proteins (IDPs). Despite their lack of stable secondary or tertiary structure, IDPs are prevalent in all forms of life and perform myriad cellular functions, including signaling and regulation. Importantly, disruption of IDP homeostasis is associated with numerous human diseases, including cancer and neurodegeneration. Despite wide recognition of IDPs, the molecular mechanisms underlying their functions are not fully understood. Here we review the structural features and disorder-function relationships for p21 and p27, two cyclin-dependent kinase (Cdk) regulators involved in controlling cell division and fate. Studies of p21 bound to Cdk2/cyclin A revealed that a helix stretching mechanism mediates binding promiscuity. Further, investigations of Tyr88-phosphorylated p27 identified a signaling conduit that controls cell division and is disrupted in certain cancers. These mechanisms rely upon a balance between nascent structure in the free state, induced folding upon binding, and persistent flexibility within functional complexes. Although these disorder-function relationships are likely to be recapitulated in other IDPs, it is also likely that the vocabulary of their mechanisms is much more extensive than is currently understood. Further study of the physical properties of IDPs and elucidation of their links with function are needed to fully understand the mechanistic language of IDPs.

Sign in / Sign up

Export Citation Format

Share Document