Two proteins with the same structure respond very differently to mutation: the role of plasticity in protein stability.
As part of a systematic study of the folding of protein structural families we compare the effect of mutation in two closely related fibronectin type III (fnIII) domains, the tenth fnIII domain of human fibronectin (FNfn10) and the third fnIII domain of human tenascin (TNfn3). This comparison of the two related proteins allows us to distinguish any anomalous response to mutation. Although they have very similar structures, the effect of mutation is very different. TNfn3 behaves like a "typical" protein, with changes in free energy correlated to the number of contacts lost on mutation. The loss of free energy upon mutation is significantly lower for FNfn10, particularly mutations of residues in the A, B and G strands. Remarkably, some of the residues involved are completely buried and closely packed in the core. In FNfn10 the regions of the protein that can accommodate mutation have previously been shown to be mobile. We propose that there is a "plasticity" in the peripheral regions of FNfn10 that allows it to rearrange to minimise the effect of mutations. This study emphasises the difficulties that might arise when making generalisations from a single member of a protein family.
Cota
E
E
Cambridge University Chemical Laboratory, MRC Centre for Protein Engineering, Lensfield Road, Cambridge, CB2 1EW, UK.
Hamill
S J
SJ
Fowler
S B
SB
Clarke
J
J
D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D001665:Binding Sites; D003903:Deuterium / Q000378:metabolism; D005353:Fibronectins / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D019791:Guanidine / Q000494:pharmacology; D006801:Humans; D007700:Kinetics; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D018583:Pliability; D011489:Protein Denaturation / Q000187:drug effects; D017510:Protein Folding; D017434:Protein Structure, Tertiary / Q000187:drug effects; D011522:Protons; D016415:Sequence Alignment; D017384:Sequence Deletion; D012997:Solvents; D019063:Tenascin / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D013816:Thermodynamics
D005353:Fibronectins; D011522:Protons; D012997:Solvents; D019063:Tenascin; D003903:Deuterium; D019791:Guanidine