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Cryptic amyloidogenic regions in intrinsically disordered proteins: Function and disease association
Jaime Santos1, Irantzu Pallarès1, Valentín Iglesias1
1Institut de Biotecnologia i Biomedicina and Departament de Bioquímica i Biologia Molecular, Universitat Autònoma de Barcelona, Bellaterra, Barcelona, Spain.
Computational and Structural Biotechnology Journal
|September 16, 2021
Summary
Cryptic amyloidogenic regions (CARs) are common in intrinsically disordered regions (IDRs) and linked to protein function and malfunction. These polar regions may have been crucial for protein evolution at life's origins.
Area of Science:
- Biochemistry
- Molecular Biology
- Protein Science
Background:
- Amyloid conformation is a fundamental protein state, with aggregation propensity a generic polypeptide property.
- Previous studies identified amyloidogenic regions, focusing on hydrophobic stretches in ordered proteins.
- Intrinsically disordered regions (IDRs) were largely overlooked in amyloidogenicity research.
Purpose of the Study:
- To investigate the prevalence and nature of cryptic amyloidogenic regions (CARs) within intrinsically disordered regions (IDRs).
- To explore the functional and potentially detrimental roles of CARs in intrinsically disordered proteins (IDPs).
- To hypothesize the evolutionary significance of CARs in early life.
Main Methods:
- Bioinformatic analysis of proteomes to identify polar, cryptic amyloidogenic regions in IDRs.
- Comparative analysis of CAR distribution and association with protein function and malfunction.
- Literature review and theoretical modeling to support evolutionary hypotheses.
Main Results:
- Cryptic amyloidogenic regions (CARs) are widespread in intrinsically disordered regions (IDRs).
- CARs are associated with the function of intrinsically disordered proteins (IDPs), particularly in protein-protein interactions.
- The presence of CARs is also linked to a risk of protein malfunction.
Conclusions:
- Polar CARs are a significant feature of IDRs, contributing to both protein function and dysfunction.
- Ancestral CARs may have served as critical functional interaction sites, playing a key role in protein evolution.
- Understanding CARs offers insights into the origins of life and protein evolution.
Keywords:
APR, Aggregation-prone regionAggregationAmyloidCARs, Cryptic amyloidogenic regionsCD, Circular dichroismCR, Congo redEvolutionFTIR, Fourier transform infraredIDPs, Intrinsically disordered proteinsIDRs, Intrinsically disordered regionsIntrinsically disordered proteinsPBS, Phosphate buffer salinePPI, Protein-protein interactionsProtein disorderProtein–protein interactionsRb, Retinoblastoma associated proteinsRbC, Core region of RbTEM, Transmission electron microscopyTh-T, Thioflavin-T
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