bims-indpro 2022-05-29 papers

bims-indpro

Biomed News

on Intrinsically disordered proteins

Issue of 2022–05–29
seventeen papers selected by
Sara Mingu, Johannes Gutenberg University

Theater in the Self-Cleaning Cell: Intrinsically Disordered Proteins or Protein Regions Acting with Membranes in Autophagy.
Multi-level analysis of intrinsically disordered protein docking methods.
Disordered regions flanking the binding interface modulate affinity between CBP and NCOA.
N6-methyladenosine-modified RNA acts as a molecular glue that drives liquid-liquid phase separation in plants.
Phase separation of Dri1 contributes to heterochromatin formation in Schizosaccharomyces pombe.
An intrinsically disordered protein region encoded by the human disease gene CLEC16A regulates mitophagy.
Exploring Nearest Neighbor Interactions and Their Influence on the Gibbs Energy Landscape of Unfolded Proteins and Peptides.
Intrinsically disordered regions couple the ligand binding and kinase activation of Trk neurotrophin receptors.
α-Synuclein fibrils explore actin mediated macropinocytosis for cellular entry into model neuroblastoma neurons.
Structural Insights into the Intrinsically Disordered GPCR C-Terminal Region, Major Actor in Arrestin-GPCR Interaction.
Influence of ion specificity and concentration on the conformational transition of intrinsically disordered sheep prion peptide.
The CD8α hinge is intrinsically disordered with a dynamic exchange that includes proline cis-trans isomerization.
Extracellular Alpha-Synuclein: Mechanisms for Glial Cell Internalization and Activation.
Monitoring Protein Global and Local Parameters in Unfolding and Binding Studies: The Extended Applicability of the Diffusion Coefficient─Molecular Size Empirical Relations.
Pleiotrophin Interaction with Synthetic Glycosaminoglycan Mimetics.
Randomizing of Oligopeptide Conformations by Nearest Neighbor Interactions between Amino Acid Residues.
Type C mutation of nucleophosmin 1 acute myeloid leukemia: Consequences of intrinsic disorder.

Membranes (Basel). 2022 Apr 24. pii: 457. [Epub ahead of print]12(5):

Theater in the Self-Cleaning Cell: Intrinsically Disordered Proteins or Protein Regions Acting with Membranes in Autophagy.

Hana Popelka, Vladimir N Uversky.

  Intrinsically disordered proteins and protein regions (IDPs/IDPRs) are mainly involved in signaling pathways, where fast regulation, temporal interactions, promiscuous interactions, and assemblies of structurally diverse components including membranes are essential. The autophagy pathway builds, de novo, a membrane organelle, the autophagosome, using carefully orchestrated interactions between proteins and lipid bilayers. Here, we discuss molecular mechanisms related to the protein disorder-based interactions of the autophagy machinery with membranes. We describe not only membrane binding phenomenon, but also examples of membrane remodeling processes including membrane tethering, bending, curvature sensing, and/or fragmentation of membrane organelles such as the endoplasmic reticulum, which is an important membrane source as well as cargo for autophagy. Summary of the current state of knowledge presented here will hopefully inspire new studies. A profound understanding of the autophagic protein-membrane interface is essential for advancements in therapeutic interventions against major human diseases, in which autophagy is involved including neurodegeneration, cancer as well as cardiovascular, metabolic, infectious, musculoskeletal, and other disorders.

Keywords:  amphipathic helix; disorder prediction; hydrophobic finger; intrinsically disordered protein; intrinsically disordered protein region; lipid bilayer; membrane binding; membrane fragmentation; membrane remodeling; membrane tethering; protein–protein interactions

DOI:  https://doi.org/10.3390/membranes12050457
Methods. 2022 May 21. pii: S1046-2023(22)00120-7. [Epub ahead of print]

Multi-level analysis of intrinsically disordered protein docking methods.

Jacob Verburgt, Zicong Zhang, Daisuke Kihara.

  Intrinsically Disordered Proteins (IDPs) are a class of proteins in which at least some region of the protein does not possess any stable structure in solution in the physiological condition but may adopt an ordered structure upon binding to a globular receptor. These IDP-receptor complexes are thus subject to protein complex modeling in which computational techniques are applied to accurately reproduce the IDP ligand-receptor interactions. This often exists in the form of protein docking, in which the 3D structures of both the subunits are known, but the position of the ligand relative to the receptor is not. Here, we evaluate the performance of three IDP-receptor modeling tools with metrics that characterize the IDP-receptor interface at various resolutions. We show that all three methods are able to properly identify the general binding site, as identified by lower resolution metrics, but begin to struggle with higher resolution metrics that capture biophysical interactions.

Keywords:  Alphafold-Multimer; CABS-Dock; Computational methods; IDP-LZerD; Intrinsically disordered protein; Protein docking; Protein structure prediction; idp; idp-receptor complex

DOI:  https://doi.org/10.1016/j.ymeth.2022.05.006
J Mol Biol. 2022 May 20. pii: S0022-2836(22)00223-6. [Epub ahead of print] 167643

Disordered regions flanking the binding interface modulate affinity between CBP and NCOA.

Elin Karlsson, Jan Schnatwinkel, Cristina Paissoni, Eva Andersson, Christian Herrmann, Carlo Camilloni, Per Jemth.

  Recognition motifs that mediate protein-protein interactions are usually embedded within longer intrinsically disordered regions. While binding interfaces involving the recognition motif in such interactions are well studied, less is known about the role of disordered regions flanking the motifs. The interaction between the transcriptional co-activators NCOA3 (ACTR) and CBP is mediated by coupled binding and folding of the two domains CID and NCBD. Here, we used circular dichroism and kinetics to directly quantify the contribution of the adjacent flanking regions of CID to its interaction with NCBD. Using N- and C-terminal combinatorial variants we found that the flanking regions promote binding in an additive fashion while retaining a large degree of disorder in the complex. Experiments at different ionic strengths demonstrated that the increase in affinity is not mediated by electrostatic interactions from the flanking regions. Instead, site-directed mutagenesis and molecular dynamics simulations suggest that binding is promoted by short-lived non-specific hydrophobic contacts between the flanking regions and NCBD. Our findings are consistent with highly frustrated interactions outside of the canonical binding interface resulting in a slightly energetically favorable fuzzy binding. Modulation of affinity via flanking regions could represent a general mechanism for functional regulation by intrinsically disordered protein regions.

Keywords:  Affinity; Binding motif; Flanking regions; Intrinsically disordered proteins; protein interactions

DOI:  https://doi.org/10.1016/j.jmb.2022.167643
Plant Signal Behav. 2022 Dec 31. 17(1): 2079308

N6-methyladenosine-modified RNA acts as a molecular glue that drives liquid-liquid phase separation in plants.

Hong Gil Lee, Jiwoo Kim, Pil Joon Seo.

  Liquid-like condensates are organized by multivalent intrinsically disordered proteins and RNA molecules. We here demonstrate that N6-methyladenosine (m6A)-modified RNA is widespread in establishing diverse plant cell condensates. Several m6A-reader proteins contain putative prion-like domains, and the ect2/3/4 mutant exhibited reduced formation of key nuclear and cytoplasmic condensates in Arabidopsis.

Keywords:  ECT; Liquid-liquid phase separation; m6A modification; m6A reader

DOI:  https://doi.org/10.1080/15592324.2022.2079308
MicroPubl Biol. 2022 ;2022

Phase separation of Dri1 contributes to heterochromatin formation in Schizosaccharomyces pombe.

Hyoju Ban, Wenqi Sun, Yong Chen, Fei Li.

The RNA binding protein Dri1 facilitates heterochromatin assembly via the RNAi pathway and histone deacetylases (HDAC). Dri1 contains an intrinsically disordered region (IDR) and three zinc fingers at its C-terminus, which are important for its role in heterochromatin silencing. Both IDR and zinc fingers have been implicated in mediating liquid-liquid phase separation (LLPS). In this study, we investigated the phase separation properties of Dri1. We observed that Dri1 undergoes phase separation in vitro . Dri1 also exhibits liquid-like behavior in vivo . Combined with our previous findings, our data support a model in which the phase-separated condensates formed by Dri1 may help recruit RNAi components and HDAC to mediate heterochromatin assembly.

DOI: https://doi.org/10.17912/micropub.biology.000559
Autophagy. 2022 May 23.

An intrinsically disordered protein region encoded by the human disease gene CLEC16A regulates mitophagy.

Morgan A Gingerich, Xueying Liu, Biaoxin Chai, Gemma L Pearson, Michael P Vincent, Tracy Stromer, Jie Zhu, Vaibhav Sidarala, Aaron Renberg, Debashish Sahu, Daniel J Klionsky, Santiago Schnell, Scott A Soleimanpour.

  CLEC16A regulates mitochondrial health through mitophagy and is associated with over 20 human diseases. However, the key structural and functional regions of CLEC16A, and their relevance for human disease, remain unknown. Here, we report that a disease-associated CLEC16A variant lacks a C-terminal intrinsically disordered protein region (IDPR) that is critical for mitochondrial quality control. IDPRs comprise nearly half of the human proteome, yet their mechanistic roles in human disease are poorly understood. Using carbon detect NMR, we find that the CLEC16A C terminus lacks secondary structure, validating the presence of an IDPR. Loss of the CLEC16A C-terminal IDPR in vivo impairs mitophagy, mitochondrial function, and glucose-stimulated insulin secretion, ultimately causing glucose intolerance. Deletion of the CLEC16A C-terminal IDPR increases CLEC16A ubiquitination and degradation, thus impairing assembly of the mitophagy regulatory machinery. Importantly, CLEC16A stability is dependent on proline bias within the C-terminal IDPR, but not amino acid sequence order or charge. Together, we elucidate how an IDPR in CLEC16A regulates mitophagy and implicate pathogenic human gene variants that disrupt IDPRs as novel contributors to diabetes and other CLEC16A-associated diseases.

Keywords:  Diabetes; NMR; insulin; mitophagy; splicing

DOI:  https://doi.org/10.1080/15548627.2022.2080383
Int J Mol Sci. 2022 May 18. pii: 5643. [Epub ahead of print]23(10):

Exploring Nearest Neighbor Interactions and Their Influence on the Gibbs Energy Landscape of Unfolded Proteins and Peptides.

Reinhard Schweitzer-Stenner.

  The Flory isolated pair hypothesis (IPH) is one of the corner stones of the random coil model, which is generally invoked to describe the conformational dynamics of unfolded and intrinsically disordered proteins (IDPs). It stipulates, that individual residues sample the entire sterically allowed space of the Ramachandran plot without exhibiting any correlations with the conformational dynamics of its neighbors. However, multiple lines of computational, bioinformatic and experimental evidence suggest that nearest neighbors have a significant influence on the conformational sampling of amino acid residues. This implies that the conformational entropy of unfolded polypeptides and proteins is much less than one would expect based on the Ramachandran plots of individual residues. A further implication is that the Gibbs energies of residues in unfolded proteins or polypeptides are not additive. This review provides an overview of what is currently known and what has yet to be explored regarding nearest neighbor interactions in unfolded proteins.

Keywords:  chemical shifts and J-coupling; conformational entropy; isolated pair hypothesis; nearest neighbor interactions; unfolded proteins

DOI:  https://doi.org/10.3390/ijms23105643
iScience. 2022 Jun 17. 25(6): 104348

Intrinsically disordered regions couple the ligand binding and kinase activation of Trk neurotrophin receptors.

Erik F Kot, María L Franco, Ekaterina V Vasilieva, Alexandra V Shabalkina, Alexander S Arseniev, Sergey A Goncharuk, Konstantin S Mineev, Marçal Vilar.

  Receptor tyrosine kinases (RTKs) are key players in development and several diseases. Understanding the molecular mechanism of RTK activation by its ligand could lead to the design of new RTK inhibitors. How the extracellular domain is coupled to the intracellular kinase domain is a matter of debate. Ligand-induced dimerization and ligand-induced conformational change of pre-formed dimers are two of the most proposed models. Recently we proposed that TrkA, the RTK for nerve growth factor (NGF), is activated by rotation of the transmembrane domain (TMD) pre-formed dimers upon NGF binding. However, one of the unsolved issues is how the ligand binding is conformationally coupled to the TMD rotation if unstructured extracellular juxtamembrane (eJTM) regions separate them. Here we use nuclear magnetic resonance in bicelles and functional studies to demonstrate that eJTM regions from the Trk family are intrinsically disordered and couple the ligand-binding domains and TMDs possibly via the interaction with NGF.

Keywords:  Molecular biology; Structural biology; Three-dimensional reconstruction of biomoleculair structures

DOI:  https://doi.org/10.1016/j.isci.2022.104348
Traffic. 2022 May 23.

α-Synuclein fibrils explore actin mediated macropinocytosis for cellular entry into model neuroblastoma neurons.

Pravin Hivare, Joshna Gadhavi, Dhiraj Bhatia, Sharad Gupta.

  Alpha-Synuclein (α-Syn), an intrinsically disordered protein (IDP), is associated with neurodegenerative disorders, including Parkinson's disease (PD) or other α-synucleinopathies. Recent investigations propose the transmission of α-Syn protein fibrils, in a prion-like manner, by entering proximal cells to seed further fibrillization in PD. Despite the recent advances, the mechanisms by which extracellular protein aggregates internalize into the cells remain poorly understood. Using a simple cell-based model of human neuroblastoma-derived differentiated neurons, we present the cellular internalization of α-Syn PFF to check cellular uptake and recycling kinetics along with the standard endocytic markers Transferrin (Tf) marking clathrin-mediated endocytosis (CME) and Galectin3 (Gal3) marking clathrin-independent endocytosis (CIE). Specific inhibition of endocytic pathways using chemical inhibitors reveals no significant involvement of CME, CIE, and caveolae-mediated endocytosis (CvME). A substantial reduction in cellular uptake was observed after perturbation of actin polymerization and treatment with macropinosomes inhibitor. Our results show that α-Syn PFF mainly internalizes into the SH-SY5Y cells and differentiated neurons via the macropinocytosis pathway. The elucidation of the molecular and cellular mechanism involved in the α-Syn PFF internalization will help improve the understanding of α-synucleinopathies including PD, and further design specific inhibitors for the same.

Keywords:  Differentiated neurons; Endocytosis; Internalization; Neuroblastoma; Parkinson's disease; Preformed-Fibrils (PFF); SH-SY5Y; α-Synuclein

DOI:  https://doi.org/10.1111/tra.12859
Biomolecules. 2022 Apr 21. pii: 617. [Epub ahead of print]12(5):

Structural Insights into the Intrinsically Disordered GPCR C-Terminal Region, Major Actor in Arrestin-GPCR Interaction.

Myriam Guillien, Assia Mouhand, Aurélie Fournet, Amandine Gontier, Aleix Martí Navia, Tiago N Cordeiro, Frédéric Allemand, Aurélien Thureau, Jean-Louis Banères, Pau Bernadó, Nathalie Sibille.

  Arrestin-dependent pathways are a central component of G protein-coupled receptor (GPCRs) signaling. However, the molecular processes regulating arrestin binding are to be further illuminated, in particular with regard to the structural impact of GPCR C-terminal disordered regions. Here, we used an integrated biophysical strategy to describe the basal conformations of the C-terminal domains of three class A GPCRs, the vasopressin V2 receptor (V2R), the growth hormone secretagogue or ghrelin receptor type 1a (GHSR) and the β2-adernergic receptor (β2AR). By doing so, we revealed the presence of transient secondary structures in these regions that are potentially involved in the interaction with arrestin. These secondary structure elements differ from those described in the literature in interaction with arrestin. This suggests a mechanism where the secondary structure conformational preferences in the C-terminal regions of GPCRs could be a central feature for optimizing arrestins recognition.

Keywords:  GPCR; NMR; arrestin; intrinsically disordered proteins or regions (IDPs/IDRs)

DOI:  https://doi.org/10.3390/biom12050617
Chemphyschem. 2022 May 27.

Influence of ion specificity and concentration on the conformational transition of intrinsically disordered sheep prion peptide.

Omkar Singh, Bratin Kumar Das, Debashree Chakraborty.

  The structural sensitivity of the IDPs with the ions has been observed experimentally; however, it is still unclear how the presence of different metal ions affects structural stability. We performed atomistic molecular dynamics simulation of sheep prion peptide (142-167) in presence of different monovalent, divalent ions at various concentrations to find out the effect of the size, charge, and ionic concentration on the structure of the peptide. It is found that Li + ions have a higher survival probability compared to Na + , K + and Mg2 + affecting the solvation structure of the protein leading to the alpha-helix structure. At high concentration, due to the increase in the ion-solvent and ion-counter interactions, the effect of the ions is screened on the surface of the protein and hence no ion specificity is observed. This study demonstrates how ions can be used to regulate the protein structure and function that can help in designing drugs.

Keywords:  Atomistic MD simulation; Intrinsically disordered protein; Preferential binding affinity of ions; Prion Peptide; alpha to beta transition

DOI:  https://doi.org/10.1002/cphc.202200211
J Magn Reson. 2022 May 13. pii: S1090-7807(22)00092-1. [Epub ahead of print]340 107234

The CD8α hinge is intrinsically disordered with a dynamic exchange that includes proline cis-trans isomerization.

Xiang Chen, Justin M Mirazee, Katarzyna A Skorupka, Hiroshi Matsuo, Philippe Youkharibache, Naomi Taylor, Kylie J Walters.

  T cells engineered to express artificial chimeric antigen receptors (CARs) that selectively target tumor-specific antigens or deleterious cell types offer transformative therapeutic possibilities. CARs contain an N-terminal extracellular antigen recognition domain, C-terminal intracellular signal transduction domains, and connecting hinge and transmembrane regions, each of which have been varied to optimize targeting and minimize toxicity. We find that a CD22-targeting CAR harboring a CD8α hinge (H) exhibits greater cytotoxicity against a low antigen density CD22+ leukemia as compared to an equivalent CAR with a CD28 H. We therefore studied the biophysical and dynamic properties of the CD8α H by nuclear magnetic resonance (NMR) spectroscopy. We find that a large region of the CD8α H undergoes dynamic chemical exchange between distinct and observable states. This exchanging region contains proline residues dispersed throughout the sequence that undergo cis-trans isomerization. Up to four signals of differing intensity are observed, with the most abundantly populated being intrinsically disordered and with all prolines in the trans isomerization state. The lesser populated states all contain cis prolines and evidence of local structural motifs. Altogether, our data suggest that the CD8α H lacks long-range structural order but has local structural motifs that transiently exchange with a dominant disordered state. We propose that structural plasticity and local structural motifs promoted by cis proline states within the CD8α H are important for relaying and amplifying antigen-binding effects to the transmembrane and signal transduction domains.

Keywords:  CAR T-cell; CD8; Intrinsically disordered proteins; Linker; Proline isomerization

DOI:  https://doi.org/10.1016/j.jmr.2022.107234
Biomolecules. 2022 Apr 30. pii: 655. [Epub ahead of print]12(5):

Extracellular Alpha-Synuclein: Mechanisms for Glial Cell Internalization and Activation.

Cecilia Chavarría, Rodrigo Ivagnes, José M Souza.

  Alpha-synuclein (α-syn) is a small protein composed of 140 amino acids and belongs to the group of intrinsically disordered proteins. It is a soluble protein that is highly expressed in neurons and expressed at low levels in glial cells. The monomeric protein aggregation process induces the formation of oligomeric intermediates and proceeds towards fibrillar species. These α-syn conformational species have been detected in the extracellular space and mediate consequences on surrounding neurons and glial cells. In particular, higher-ordered α-syn aggregates are involved in microglial and oligodendrocyte activation, as well as in the induction of astrogliosis. These phenomena lead to mitochondrial dysfunction, reactive oxygen and nitrogen species formation, and the induction of an inflammatory response, associated with neuronal cell death. Several receptors participate in cell activation and/or in the uptake of α-syn, which can vary depending on the α-syn aggregated state and cell types. The receptors involved in this process are of outstanding relevance because they may constitute potential therapeutic targets for the treatment of PD and related synucleinopathies. This review article focuses on the mechanism associated with extracellular α-syn uptake in glial cells and the consequent glial cell activation that contributes to the neuronal death associated with synucleinopathies.

Keywords:  astrocytes; extracellular alpha-synuclein; fibrils; microglia; oligodendrocytes; oligomers

DOI:  https://doi.org/10.3390/biom12050655
Anal Chem. 2022 May 26.

Monitoring Protein Global and Local Parameters in Unfolding and Binding Studies: The Extended Applicability of the Diffusion Coefficient─Molecular Size Empirical Relations.

Csenge Lilla Szabó, Fanni Sebák, Andrea Bodor.

Protein unfolding and denaturation are main issues in biochemical and pharmaceutical research. Using a global parameter, the translational diffusion coefficient D, folded, unfolded, and intrinsically disordered proteins of a given molar mass M can be distinguished based on their distinct hydrodynamic properties. For broader applications, we provide generalized, PFG-NMR-based empirical D-M relations validated at different temperatures and ready to use with the corresponding corrections in different media. We demonstrate that these relations enable a more accurate molecular mass determination and show fewer potential errors than those of the common methods based on small-molecular diffusion standards. We monitor unfolding of three model proteins using 8 M urea and dimethyl sulfoxide (DMSO)-water mixtures as denaturing agents, highlighting the effect of disulfide bonds. Denaturation in 8 M urea is pH-dependent; in addition, for proteins with highly stable disulfide bonds, a reducing agent (TCEP) is required to achieve complete unfolding. Regarding the effect of local parameters, we show that at low DMSO concentrations─common conditions in pharmaceutical binding studies─the PFG-NMR-derived global parameters are not significantly affected. Still, the atomic environments can change, and the bound solvent molecule can inhibit the binding of a partner molecule. Using proteins with natural isotopic abundance, this effect can be proven by fast 1H-15N 2D correlation spectra. Our results enable fast and easy estimation of protein molecular mass and the degree of folding in various media; moreover, the effect of the cosolvent on the atomic-level structure can be traced without the need of isotope labeling.

DOI: https://doi.org/10.1021/acs.analchem.2c00481
Pharmaceuticals (Basel). 2022 Apr 19. pii: 496. [Epub ahead of print]15(5):

Pleiotrophin Interaction with Synthetic Glycosaminoglycan Mimetics.

Jonathan R Miles, Xu Wang, Jose L de Paz, Pedro M Nieto.

  Chondroitin sulfate (CS) E is the natural ligand for pleiotrophin (PTN) in the central nervous system (CNS) of the embryo. Some structures of PTN in solution have been solved, but no precise location of the binding site has been reported yet. Using 15N-labelled PTN and HSQC NMR experiments, we studied the interactions with a synthetic CS-E tetrasaccharide corresponding to the minimum binding sequence. The results agree with the data for larger GAG (glycosaminoglycans) sequences and confirm our hypothesis that a synthetic tetrasaccharide is long enough to fully interact with PTN. We hypothesize that the central region of PTN is an intrinsically disordered region (IDR) and could modify its properties upon binding. The second tetrasaccharide has two benzyl groups and shows similar effects on PTN. Finally, the last measured compound aggregated but beforehand, showed a behavior compatible with a slow exchange in the NMR time scale. We propose the same binding site and mode for the tetrasaccharides with and without benzyl groups.

Keywords:  15N-HSQC; NMR; chondroitin sulphate type E; glycosaminoglycan

DOI:  https://doi.org/10.3390/ph15050496
Biomolecules. 2022 May 11. pii: 684. [Epub ahead of print]12(5):

Randomizing of Oligopeptide Conformations by Nearest Neighbor Interactions between Amino Acid Residues.

Reinhard Schweitzer-Stenner, Bridget Milorey, Harald Schwalbe.

  Flory's random coil model assumes that conformational fluctuations of amino acid residues in unfolded poly(oligo)peptides and proteins are uncorrelated (isolated pair hypothesis, IPH). This implies that conformational energies, entropies and solvation free energies are all additive. Nearly 25 years ago, analyses of coil libraries cast some doubt on this notion, in that they revealed that aromatic, but also β-branched side chains, could change the 3J(HNHCα) coupling of their neighbors. Since then, multiple bioinformatical, computational and experimental studies have revealed that conformational propensities of amino acids in unfolded peptides and proteins depend on their nearest neighbors. We used recently reported and newly obtained Ramachandran plots of tetra- and pentapeptides with non-terminal homo- and heterosequences of amino acid residues to quantitatively determine nearest neighbor coupling between them with a Ising type model. Results reveal that, depending on the choice of amino acid residue pairs, nearest neighbor interactions either stabilize or destabilize pairs of polyproline II and β-strand conformations. This leads to a redistribution of population between these conformations and a reduction in conformational entropy. Interactions between residues in polyproline II and turn(helix)-forming conformations seem to be cooperative in most cases, but the respective interaction parameters are subject to large statistical errors.

Keywords:  Ramachandran distributions; intrinsically disordered proteins; isolated pair hypothesis; model peptides; nearest neighbor interactions

DOI:  https://doi.org/10.3390/biom12050684
Biochim Biophys Acta Gen Subj. 2022 May 18. pii: S0304-4165(22)00091-5. [Epub ahead of print]1866(8): 130173

Type C mutation of nucleophosmin 1 acute myeloid leukemia: Consequences of intrinsic disorder.

Sara La Manna, Daniele Florio, Concetta Di Natale, Elena Lagreca, Teresa Sibillano, Cinzia Giannini, Daniela Marasco.

   BACKGROUND: Nucleophosmin 1 (NPM1) protein is a multifunctional nucleolar chaperone and its gene is the most frequently mutated in Acute Myeloid Leukemia (AML). AML mutations cause the unfolding of the C-terminal domain (CTD) and the protein delocalizing in the cytosol (NPM1c+). Marked aggregation endowed with an amyloid character was assessed as consequences of mutations.
SCOPE: Herein we analyzed the effects of type C mutation on two protein regions: i) a N-terminal extended version of the CTD, named Cterm_mutC and ii) a shorter polypeptide including the sequences of the second and third helices of the CTD, named H2_mutC.
MAJOR CONCLUSIONS: Both demonstrated able to self-assembly with different kinetics and conformational intermediates and to provide fibers presenting large flexible regions.
GENERAL SIGNIFICANCE: The present study adds a new piece of knowledge to the effects of AML-mutations on structural biology of Nucleophosmin 1, that could be exploited in therapeutic interventions targeting selectively NPMc+.

Keywords:  Acute myeloid leukemia; Aggregation; Intrinsically disordered regions; Wide-Angle X-ray Scattering

DOI:  https://doi.org/10.1016/j.bbagen.2022.130173