One of the hGal-1 mutants that may be clinically
significant is the C2S mutant. Because the oxygen from the
hydroxyl group in Ser is a weaker reducing agent than the
sulfur from the thiol group in Cys, the mutant is in a less
reduced state and thus should be more resistant to oxidation.
The C2S mutant has been observed to be more stable than wild
type hGal-1 (WT) (Hirabayashi et al., 1991) and such
stability is promising in terms of clinical applications.
A significant conformational change between the WT
and the C2S mutant involves the orientation of Asp123 and the
connections it makes with Val131
and Cys2 (Or Ser2, in the case of
directs Asp123 towards
F1 and forms a hydrogen bond with Val131.
, Asp123 faces toward Ser2 and distorts
the connecting loops. Though this conformational change is
distant from the CRD, it significantly lowers hGal-1’s
affinity for carbohydrates.
Likewise, such conformational change is also present
. Furthermore, the R111H substitution is also responsible for a
direct alteration of the CRD. In
Arg111 forms hydrogen bonds with the
hydroxyl group of Ser62 and with
the carbonyl group of Thr70. In
contrast, with the
, Ser62 and Thr70 establish hydrogen bonds with the ring of His111
and consequently distorts the loops connecting F4-F5, F3-F4,
F3-F6b, S5-S6a, and S4-S5. The distortion shifts
- two highly conserved amino acid residues involved in carbohydrate
recognition - and weakens its ability to bind carbohydrates.
Camby, I., Mercier, M. L., Lefranc, F.,
and Kiss, R. (2006). Galectin-1: a small protein with major
functions. Glycobiology, 16(11), pp. 137-157.
Hirabayashi, J. & Kasai, K.-I.
(1991). Effect of amino acid substitution by site-directed
mutagenesis on the carbohydrate recognition and stability of
human 14-kDa b-galactoside-binding lectin. Jounal of
Biological Chemistry, 266, pp. 23648–23653.
Lopez-Lucendo, M. F., Solis, D., Andre,
S., Hirabayashi, S. A. J., Kasai, K., Gabius, H., and
Romero, A. (2004). Growth-regulatory Human Galectin-1:
Crystallographic Characterisation of the Structural Changes
Induced by Single-site Mutations and their Impact on the
Thermodynamics of Ligand Binding. Journal of Molecular
Biology, 343(4), pp. 957-970.
Barondes, S. H., Cooper, D., Gitt, M.
A., and Leffler, H. (1994). Galectins: Structure and
Function of a Large Family of Animal Lectins. The
Journal of Biological Chemistry, 269(33), >
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