This is a concluding part of the three-part article from a series of reviews on the abundance and roles of intrinsic
disorder in milk proteins. In this paper, we describe the peculiarities of metal binding to a multifunctional milk protein,
α-lactalbumin, which has two domains, a large α-helical domain and a small β-sheet domain connected by a calcium binding
loop. It is known that in addition to four disulfide bonds, the native fold of this protein is stabilized by binding of a
calcium ion. In fact, although in various mammals, α-lactalbumins are rather poorly conserved possessing the overall sequence
identity of ~16%, the positions of all eight cysteines and a calcium binding site (residues DKFLDDDITDDI in
human protein) are strongly conserved. Curiously, this conserved calcium binding loop is located within a region with increased
structural flexibility. Besides canonical calcium binding, α-lactalbumin is known to interact with other metals,
such as zinc (for which it has a specific binding site), and, in its apo-form, it can bind other divalent and monovalent cations.
The binding of Mg2+, Na+, and K+ to the Ca2+ site increases α-lactalbumin stability against action of heat and various
denaturing agents, with the higher stabilization effects being imposed by the stronger bound metal ions.