Tuning the mechanical stability of fibronectin type III modules through sequence variations.
Cells can switch the functional states of extracellular matrix proteins by stretching them while exerting mechanical force. Using steered molecular dynamics, we investigated how the mechanical stability of FnIII modules from the cell adhesion protein fibronectin is affected by natural variations in their amino acid sequences. Despite remarkably similar tertiary structures, FnIII modules share low sequence homology. Conversely, the sequence homology for the same FnIII module across multiple species is notably higher, suggesting that sequence variability is functionally significant. Our studies find that the mechanical stability of FnIII modules can be tuned through substitutions of just a few key amino acids by altering access of water molecules to hydrogen bonds that break early in the unfolding pathway. Furthermore, the FnIII hierarchy of mechanical unfolding can be changed by environmental conditions, such as pH for FnIII10, or by forming complexes with other molecules, such as heparin binding to FnIII13.
Craig
David
D
Department of Bioengineering, University of Washington, Seattle, WA 98195, USA.
Gao
Mu
M
Schulten
Klaus
K
Vogel
Viola
V
D000595:Amino Acid Sequence; D005353:Fibronectins / Q000737:chemistry* / Q000235:genetics; D006493:Heparin / Q000737:chemistry; D006860:Hydrogen Bonding; D006863:Hydrogen-Ion Concentration; D008958:Models, Molecular; D008969:Molecular Sequence Data; D017510:Protein Folding; D017434:Protein Structure, Tertiary / Q000235:genetics; D017386:Sequence Homology, Amino Acid
D005353:Fibronectins; D006493:Heparin