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Asparagine Repeat Peptides: Aggregation Kinetics and Comparison with Glutamine Repeats
Xiaomeng Lu1, Regina M Murphy1
1†Biophysics Program and ‡Department of Chemical and Biological Engineering, University of Wisconsin-Madison, Madison, Wisconsin 53706, United States.
Biochemistry
|July 24, 2015
Summary
Asparagine (N) repeats aggregate faster than glutamine (Q) repeats, forming β-turns and promoting rapid protein misfolding and neurodegenerative disease. This explains why N-repeats are rare in vertebrates.
Area of Science:
- Biochemistry
- Molecular Biology
- Neuroscience
Background:
- Amino acid repeat sequences, particularly glutamine (Q) and asparagine (N), are prevalent in eukaryotic proteins.
- Expanded Q-repeat domains are implicated in at least nine neurodegenerative disorders due to protein misfolding and aggregation.
- N-repeats are common in invertebrates but virtually absent in vertebrates, suggesting a selective pressure against aggregation-prone proteins in higher organisms.
Purpose of the Study:
- To investigate the aggregation properties of asparagine (N)-repeat peptides and compare them with glutamine (Q)-repeat peptides.
- To understand the biophysical differences in aggregation between N- and Q-repeat peptides.
- To explore the potential reasons for the differential distribution of N- and Q-repeats in vertebrates and invertebrates.
Main Methods:
- Characterization of the aggregation of synthetic peptides with variable-length asparagine repeats (12-24 residues).
- Comparative analysis of aggregation kinetics and structural properties of N-repeat peptides versus similar Q-repeat peptides.
- Conformational analysis of monomeric peptides to identify structural differences influencing aggregation.
Main Results:
- Aggregation of N-repeat peptides was found to be strongly dependent on repeat length, similar to Q-repeats.
- Substitution of glutamine with asparagine induced a subtle conformational shift in the monomer, significantly impacting aggregation rates.
- N-repeat peptides adopted β-turn structures, leading to accelerated self-assembly into globular oligomers and faster conversion into fibrillar aggregates compared to Q-repeat peptides.
Conclusions:
- Asparagine repeats exhibit distinct biophysical properties compared to glutamine repeats, favoring more rapid aggregation.
- The observed differences in aggregation kinetics and structure may explain the scarcity of N-repeats in vertebrates.
- These findings provide insights into the molecular basis of protein aggregation and its role in neurodegenerative diseases and evolution.
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