Aromatic claw: A new fold with high aromatic content that evades structural prediction

Area of Science:

• Structural biology
• Protein science
• Biophysics

Background:

• The protein Aq1974 from Aquifex aeolicus possesses a highly aromatic sequence with unusually high tryptophan content.
• Its sequence exhibits no detectable homology to known protein structures, indicating a potentially novel fold.

Purpose of the Study:

• To determine the three-dimensional solution structure of the aromatic protein Aq1974 using Nuclear Magnetic Resonance (NMR) spectroscopy.
• To characterize the novel protein fold and assess the accuracy of computational protein structure prediction methods for unique sequences.

Main Methods:

• Nuclear Magnetic Resonance (NMR) spectroscopy was employed for resonance assignment and solution structure determination.
• The determined structure was compared against predictions from the Critical Assessment of protein Structure Prediction (CASP10) competition.

Main Results:

• The NMR structure revealed a primarily alpha-helical protein with a small, two-stranded beta-sheet, forming a novel fold termed the 'Aromatic Claw'.
• Despite initial spectral indications of high beta-sheet content, the final structure was predominantly alpha-helical.
• Computational predictions in CASP10 failed to accurately predict the experimental structure, with limited correlation between prediction scores and accuracy.

Conclusions:

• The experimental determination of the novel 'Aromatic Claw' fold in Aq1974 underscores the challenges in predicting protein structure from primary sequence.
• This finding emphasizes the ongoing need for experimental structural biology to guide and improve computational protein structure prediction algorithms.