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Optimization of Synthetic Proteins: Identification of Interpositional Dependencies Indicating Structurally and/or Functionally Linked Residues
Published on: July 14, 2015
Aggregation prone regions and gatekeeping residues in protein sequences
Jacinte Beerten1, Joost Schymkowitz, Frederic Rousseau
1VIB Switch Laboratory, VIB, Leuven, Belgium.
Current Topics in Medicinal Chemistry
|January 24, 2013
Summary
Short regions in proteins (aggregation-prone regions or APRs) can cause aggregation, leading to diseases like neurodegeneration and cancer. This review explores how APRs alter cellular interactions and disease.
Area of Science:
- Biochemistry
- Molecular Biology
- Cell Biology
Background:
- Protein sequences contain aggregation-prone regions (APRs) that can initiate protein aggregation.
- Under normal conditions, APRs are shielded by protein interactions or hydrophobic cores.
- Stress, mutations, or aging can expose APRs, leading to aggregation.
Purpose of the Study:
- To review the mechanisms of APR-driven protein aggregation.
- To explain how APRs modify cellular interactions and contribute to disease.
- To discuss the evolutionary pressure on protein sequences to minimize APR aggregation.
Main Methods:
- Literature review of protein aggregation mechanisms.
- Analysis of functional effects of APR-driven aggregation in diseases.
- Discussion of molecular mechanisms contributing to gain-of-function in protein aggregates.
Main Results:
- APR aggregation leads to diverse functional effects, causing diseases like neurodegeneration and cancer.
- Protein aggregates can cause disease through loss-of-function or gain-of-function mechanisms.
- Gain-of-function arises from altered cellular interactions, such as RNA sequestration or protein entrapment.
Conclusions:
- APRs are key drivers of protein aggregation and associated diseases.
- Protein aggregation significantly rewires the cellular interactome, impacting cellular functions.
- Evolutionary selection has shaped protein sequences to reduce the aggregation potential of APRs.
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