scholarly journals Predicting aggregation-prone sequences in proteins

2014 ◽  
Vol 56 ◽  
pp. 41-52 ◽  
Author(s):  
Greet De Baets ◽  
Joost Schymkowitz ◽  
Frederic Rousseau
Keyword(s):  
Protein Quality ◽  
Amino Acid Sequences ◽  
Net Charge ◽  
Diverse Range ◽  
High Tendency ◽  
Practical Applications ◽  
Aggregation Propensity ◽  
Polypeptide Sequence ◽  
Protein Quality Control System ◽  
Aggregation Tendency

Owing to its association with a diverse range of human diseases, the determinants of protein aggregation are studied intensively. It is generally accepted that the effective aggregation tendency of a protein depends on many factors such as folding efficiency towards the native state, thermodynamic stability of that conformation, intrinsic aggregation propensity of the polypeptide sequence and its ability to be recognized by the protein quality control system. The intrinsic aggregation propensity of a polypeptide sequence is related to the presence of short APRs (aggregation-prone regions) that self-associate to form intermolecular β-structured assemblies. These are typically short sequence segments (5–15 amino acids) that display high hydrophobicity, low net charge and a high tendency to form β-structures. As the presence of such APRs is a prerequisite for aggregation, a plethora of methods have been developed to identify APRs in amino acid sequences. In the present chapter, the methodological basis of these approaches is discussed, as well as some practical applications.

Shape matters: the complex relationship between aggregation and toxicity in protein-misfolding diseases

2016 ◽  
Vol 60 (2) ◽  
pp. 181-190 ◽  
Author(s):  
Heidrun Maja Ries ◽  
Carmen Nussbaum-Krammer
Keyword(s):  
Protein Misfolding ◽  
Protein Quality ◽  
Cellular Protein ◽  
Exact Nature ◽  
High Tendency ◽  
Protein Deposits ◽  
Cellular Environment ◽  
Individual Interaction ◽  
Protein Quality Control System ◽  
Misfolding Diseases

A particular subgroup of protein-misfolding diseases, comprising Alzheimer's and Parkinson's disease, involves amyloidogenic proteins that can form alternative pathogenic conformations with a high tendency to self-assemble into oligomeric and fibrillar species. Although misfolded proteins have been clearly linked to disease, the exact nature of the toxic species remains highly controversial. Increasing evidence suggests that there is little correlation between the occurrence of macroscopic protein deposits and toxic phenotypes in affected cells and tissues. In this article, we recap amyloid aggregation pathways, describe prion-like propagation, elaborate on detrimental interactions of protein aggregates with the cellular protein quality control system and discuss why some aggregates are toxic, whereas others seem to be beneficial. On the basis of recent studies on prion strains, we reason that the specific aggregate conformation and the resulting individual interaction with the cellular environment might be the major determinant of toxicity.

Potential aggregation hot spots in recombinant human keratinocyte growth factor; a computational study

2020 ◽  
Author(s):  
Mansoureh Shahbazi Dastjerdeh ◽  
Mohammad Ali Shokrgozar ◽  
Hamzeh Rahimi ◽  
Majid Golkar
Keyword(s):  
Growth Factor ◽  
Tertiary Structure ◽  
Computational Study ◽  
Keratinocyte Growth Factor ◽  
Native State ◽  
Hydrophobic Residues ◽  
Aggregation Propensity ◽  
State Aggregation ◽  
Human Keratinocyte ◽  
Aggregation Tendency

Abstract Background: Recombinant human keratinocyte growth factor is a highly aggregation-prone therapeutic protein. The high aggregation liability of rhKGF is manifested by loss of the monomeric form of the protein and accumulation of the aggregated species even at moderate temperatures. Here, we analyzed rhKGF for its vulnerability towards aggregation by detection of aggregation-prone regions (APRs) using several sequence-based computational tools including TANGO, SolubiS, ZipperDB, AGGRESCAN, Zyggregator, Camsol, PASTA, SALSA, WALTZ, SODA, Amylpred, AMYPDB, and structure-based tools including Aggrescan3D and molecular dynamics-based spatial aggregation propensity (SAP) algorithm. Results: The sequence-based prediction of APRs in rhKGF indicated that they are mainly located at positions 10-30, 40-60, 61-66, 88-120, and 130-140 which are rich in β-branched aliphatic, hydrophobic, aromatic and Glutamine/Aspargine (Q/N) residues. Mapping on the rhKGF tertiary structure revealed that most of these residues including F16-R25, I43, E45, R47-I56, F61, Y62, N66, L88-E91, E108-F110, A112, N114, T131, and H133-T140 are surface-exposed in the natively folded protein which can promote aggregation without major unfolding event or the conformational change may occur in the oligomers composed of natively folded monomers. The other regions are buried in the native state and their contribution to non-native aggregation is mediated by a preceding unfolding event in the monomeric state of the protein. The structure-based prediction of APRs using SAP tool limited the number of identified APRs to the dynamically-exposed hydrophobic residues including V12, A50, V51, L88, I89, L90, I118, L135, and I139 mediating the native-state aggregation. Conclusion: Our analysis of APRs in rhKGF identified the regions determining the intrinsic aggregation propensity in both folded (native) and unfolded state of the protein. These regions are the candidate positions for engineering the rhKGF sequence to reduce its aggregation tendency.

scholarly journals A Crucial Role for the Protein Quality Control System in Motor Neuron Diseases

2020 ◽  
Vol 12 ◽  
Author(s):  
Riccardo Cristofani ◽  
Valeria Crippa ◽  
Maria Elena Cicardi ◽  
Barbara Tedesco ◽  
Veronica Ferrari ◽  
...  
Keyword(s):  
Quality Control ◽  
Control System ◽  
Motor Neuron ◽  
Crucial Role ◽  
Protein Quality ◽  
Protein Quality Control ◽  
Quality Control System ◽  
Motor Neuron Diseases ◽  
Protein Quality Control System

scholarly journals Antifouling (Bio)materials for Electrochemical (Bio)sensing

2019 ◽  
Vol 20 (2) ◽  
pp. 423 ◽  
Author(s):  
Susana Campuzano ◽  
María Pedrero ◽  
Paloma Yáñez-Sedeño ◽  
José Pingarrón
Keyword(s):  
Metallic Nanoparticles ◽  
Self Assembled Monolayers ◽  
Electrochemical Activation ◽  
Reaction Products ◽  
Diverse Range ◽  
Prolonged Incubation ◽  
Practical Applications ◽  
Electrochemical Biosensing ◽  
Redox Couples ◽  
Assembled Monolayers

(Bio)fouling processes arising from nonspecific adsorption of biological materials (mainly proteins but also cells and oligonucleotides), reaction products of neurotransmitters oxidation, and precipitation/polymerization of phenolic compounds, have detrimental effects on reliable electrochemical (bio)sensing of relevant analytes and markers either directly or after prolonged incubation in rich-proteins samples or at extreme pH values. Therefore, the design of antifouling (bio)sensing interfaces capable to minimize these undesired processes is a substantial outstanding challenge in electrochemical biosensing. For this purpose, efficient antifouling strategies involving the use of carbon materials, metallic nanoparticles, catalytic redox couples, nanoporous electrodes, electrochemical activation, and (bio)materials have been proposed so far. In this article, biomaterial-based strategies involving polymers, hydrogels, peptides, and thiolated self-assembled monolayers are reviewed and critically discussed. The reported strategies have been shown to be successful to overcome (bio)fouling in a diverse range of relevant practical applications. We highlight recent examples for the reliable sensing of particularly fouling analytes and direct/continuous operation in complex biofluids or harsh environments. Opportunities, unmet challenges, and future prospects in this field are also pointed out.

scholarly journals The Mitochondrial Lon Protease: Novel Functions off the Beaten Track?

Biomolecules ◽  
2020 ◽  
Vol 10 (2) ◽  
pp. 253 ◽  
Author(s):  
Wolfgang Voos ◽  
Karen Pollecker
Keyword(s):  
Mammalian Cells ◽  
Protein Quality ◽  
Proteolytic Enzymes ◽  
Mitochondrial Gene ◽  
Protective Action ◽  
Stress Conditions ◽  
Endogenous Protein ◽  
The Matrix ◽  
Beaten Track ◽  
Protein Quality Control System

To maintain organellar function, mitochondria contain an elaborate endogenous protein quality control system. As one of the two soluble energy-dependent proteolytic enzymes in the matrix compartment, the protease Lon is a major component of this system, responsible for the degradation of misfolded proteins, in particular under oxidative stress conditions. Lon defects have been shown to negatively affect energy production by oxidative phosphorylation but also mitochondrial gene expression. In this review, recent studies on the role of Lon in mammalian cells, in particular on its protective action under diverse stress conditions and its relationship to important human diseases are summarized and commented.

scholarly journals The Crystal Structure of Archaeal Nascent Polypeptide-associated Complex (NAC) Reveals a Unique Fold and the Presence of a Ubiquitin-associated Domain

2005 ◽  
Vol 280 (16) ◽  
pp. 15849-15854 ◽  
Author(s):  
Thomas Spreter ◽  
Markus Pech ◽  
Birgitta Beatrix
Keyword(s):  
Crystal Structure ◽  
Protein Quality ◽  
Structural Features ◽  
Cellular Protein ◽  
Nascent Polypeptide ◽  
Nascent Chain ◽  
Ubiquitination Pathway ◽  
Protein Quality Control System ◽  
Cytosolic Factor ◽  
Cytosolic Factors

Nascent polypeptide-associated complex (NAC) was identified in eukaryotes as the first cytosolic factor that contacts the nascent polypeptide chain emerging from the ribosome. NAC is highly conserved from yeast to humans. Mutations in NAC cause severe embryonically lethal phenotypes in mice,Drosophila,andCaenorhabditis elegans.NAC was suggested to protect the nascent chain from inappropriate early interactions with cytosolic factors. Eukaryotic NAC is a heterodimer with two subunits sharing substantial homology with each other. All sequenced archaebacterial genomes exhibit only one gene homologous to the NAC subunits. Here we present the first archaebacterial NAC homolog. It forms a homodimer, and as eukaryotic NAC it is associated with ribosomes and contacts the emerging nascent chain on the ribosome. We present the first crystal structure of a NAC protein revealing two structural features: (i) a novel unique protein fold that mediates dimerization of the complex, and (ii) a ubiquitin-associated domain that suggests a yet unidentified role for NAC in the cellular protein quality control system via the ubiquitination pathway. Based on the presented structure we propose a model for the eukaryotic heterodimeric NAC domain.

scholarly journals Truncation-Driven Lateral Association of α-Synuclein Hinders Amyloid Clearance by the Hsp70-based Disaggregase

2021 ◽  
Vol 22 (23) ◽  
pp. 12983
Author(s):  
Aitor Franco ◽  
Jorge Cuéllar ◽  
José Ángel Fernández-Higuero ◽  
Igor de la Arada ◽  
Natalia Orozco ◽  
...  
Keyword(s):  
Neurodegenerative Disorders ◽  
Protein Quality ◽  
Mechanical Action ◽  
Cellular Protein ◽  
Type B ◽  
Post Translational Modifications ◽  
Lateral Association ◽  
N Terminus ◽  
Protein Quality Control System

The aggregation of α-synuclein is the hallmark of a collective of neurodegenerative disorders known as synucleinopathies. The tendency to aggregate of this protein, the toxicity of its aggregation intermediates and the ability of the cellular protein quality control system to clear these intermediates seems to be regulated, among other factors, by post-translational modifications (PTMs). Among these modifications, we consider herein proteolysis at both the N- and C-terminal regions of α-synuclein as a factor that could modulate disassembly of toxic amyloids by the human disaggregase, a combination of the chaperones Hsc70, DnaJB1 and Apg2. We find that, in contrast to aggregates of the protein lacking the N-terminus, which can be solubilized as efficiently as those of the WT protein, the deletion of the C-terminal domain, either in a recombinant context or as a consequence of calpain treatment, impaired Hsc70-mediated amyloid disassembly. Progressive removal of the negative charges at the C-terminal region induces lateral association of fibrils and type B* oligomers, precluding chaperone action. We propose that truncation-driven aggregate clumping impairs the mechanical action of chaperones, which includes fast protofilament unzipping coupled to depolymerization. Inhibition of the chaperone-mediated clearance of C-truncated species could explain their exacerbated toxicity and higher propensity to deposit found in vivo.

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