Author:
Cheung Ngaam J.,Huang Si-Yu
Abstract
ABSTRACTNaturally co-occurring amino acids, term coevolution, in a protein family play a significant role in both protein engineering and folding, and it is expanding in recent years from the studies of the effects of single-site mutations to the complete re-design of a protein and its folding, especially in three-dimensional structure prediction. Here, to better characterize such coevolving interactions, wein silicodecipher evolutionary couplings from massive homologous sequences using spectral analysis to capture signatures that are important for specific molecular interactions and binding activities. We implement the present approach on the G7 gamma delta T-cell receptor to identify functionally important residues that contribute to its highly distinct binding mode. The analysis indicates the evolutionary signatures (highly ordered networks of coupled amino acids, termed residue communities) of the protein confirm previously identified functional sites that are relevant to dock the receptor underneath the major histocompatibility complex class I-related protein-1 (MR1) antigen presenting groove. Moreover, we analyze the correlation of inter-residue contacts with the activation states of receptors and show that contact patterns closely correlating with activation indeed coincide with these sites. The theoretical results demonstrate our method provides an alternative path towards bridging protein sequence with its function at residue-level without requiring its tertiary structure or highly accurate measurement of its biological activitiesin vivo/vitro.
Publisher
Cold Spring Harbor Laboratory