Kinetic and equilibrium unfolding experiments indicate that the VH mutation also affects VL unfolding, possibly by partially destabilizing the interface provided by VH, even though the mutation is distant from the interface.
The point mutation is distant from the K63-Ub2 interfaces with tUIM and NZF.
A cluster in tertiary structure can conceivably consist of mutations that are distant in primary structure.
Therefore, mutations that are distant from the active site have on occasion been shown to affect substrate specificity.
However, a few mutations that are distant from the active site cause severe phenotypes due to their adverse effects on the enzyme structure and function (discussed later).
Whilst it may be intuitively obvious that the study of hERG1b-specific mutations [16] or N-terminal long QT syndrome (LQTS) mutations (∼20% of hERG1a-linked LQTS mutations occur in the N-terminus [26]) warrants the study of hERG1a/1b heteromeric channels, until now there may not have been a clear rationale to adopt this approach when studying mutations that are distant from the N-terminus.
Although our hANT4 peptides contain mutations required for proper assembly and stability of the proteins in yeast mitochondrial membrane, these mutation sites are distant from the ADP/ATP binding pocket and unlikely to substantially change the substrate binding affinity per se.
The only "second-generation" variant is the double mutant N96W + H222R (number 10 in Table 2) that was expressed because the single mutant N96W had a high experimental affinity and H222R showed neutral binding behavior, while these two single mutations are sequentially distant so that we assumed that they might influence each other the least.
Although spatially the mutations introduced to disassociate CH3 dimerization are distant from the FcRn binding region in CH2-CH3, Half DVD-Ig molecules that have the F405R or other CH3-mutations exhibited significantly reduced serum half-life.
Such compensatory mutations can occur at positions that are distant from each other in space, thus, reflecting long-range interactions in proteins (Horovitz et al., 1994; Lee et al., 2008).
