ArticleBiochemistry2013
Delicate balance between functionally required flexibility and aggregation risk in a β-rich protein.
Article in Biochemistry, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
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Who cites it
10 citing papers in PubMed, 27 citations in OpenAlex.
- Combined analytical approach empowers precise spectroscopic interpretation of subcellular components of pancreatic cancer cells.Analytical and bioanalytical chemistry · 2023Article
- Impact of Intracellular Lipid Binding Proteins on Endogenous and Xenobiotic Ligand Metabolism and Disposition.Drug metabolism and disposition: the biological fate of chemicals · 2023Review
- Variabilities in global DNA methylation and β-sheet richness establish spectroscopic landscapes among subtypes of pancreatic cancer.European journal of nuclear medicine and molecular imaging · 2023Article
- Structural and Dynamic Determinants of Molecular Recognition in Bile Acid-Binding Proteins.International journal of molecular sciences · 2022Review
- Probing the local conformational flexibility in receptor recognition: mechanistic insight from an atomic-scale investigation.RSC advances · 2019Article
- Atomic force microscopy for single molecule characterisation of protein aggregation.Archives of biochemistry and biophysics · 2019Review
- Local and non-local topological information in the denatured state ensemble of a β-barrel protein.Protein science : a publication of the Protein Society · 2018Article
- Structural basis for cross-reactivity and conformation fluctuation of the major beech pollen allergen Fag s 1.Scientific reports · 2018Article
- Direct Conversion of an Enzyme from Native-like to Amyloid-like Aggregates within Inclusion Bodies.Biophysical journal · 2017Article
- Energy landscapes of functional proteins are inherently risky.Nature chemical biology · 2014Article
Corrections and comments
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Authors and funding
5 authors at 1 institution in 1 country.
Funding
Abstract
Susceptibility to aggregation is general to proteins because of the potential for intermolecular interactions between hydrophobic stretches in their amino acid sequences. Protein aggregation has been implicated in several catastrophic diseases, yet we still lack in-depth understanding about how proteins are channeled to this state. Using a predominantly β-sheet protein whose folding has been explored in detail, cellular retinoic acid-binding protein 1 (CRABP1), as a model, we have tackled the challenge of understanding the links between a protein's natural tendency to fold, 'breathe', and function with its propensity to misfold and aggregate. We identified near-native dynamic species that lead to aggregation and found that inherent structural fluctuations in the native protein, resulting in opening of the ligand-entry portal, expose hydrophobic residues on the most vulnerable aggregation-prone sequences in CRABP1. CRABP1 and related intracellullar lipid-binding proteins have not been reported to aggregate inside cells, and we speculate that the cellular concentration of their open, aggregation-prone conformations is sufficient for ligand binding but below the critical concentration for aggregation. Our finding provides an example of how nature fine-tunes a delicate balance between protein function, conformational variability, and aggregation vulnerability and implies that with the evolutionary requirement for proteins to fold and function, aggregation becomes an unavoidable but controllable risk.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.