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Alpha-lactalbumin (LALBA) is a 14.2 kDa calcium-binding protein primarily synthesized in the mammary glands, where it serves as the essential regulatory subunit of the lactose synthase enzyme complex [1]. The protein contains a high-affinity calcium-binding site that is critical for its structural stability; the binding of a single Ca²⁺ ion maintains the protein in its native, functional fold [2]. Under conditions of low calcium or low pH, alpha-lactalbumin transitions into a partially unfolded molten globule state, exposing hydrophobic surfaces [3]. In this state, it can associate with fatty acids, such as oleic acid, to form a complex known as HAMLET (Human Alpha-lactalbumin Made LEthal to Tumor cells) [4]. HAMLET exhibits selective cytotoxic activity against a wide range of cancer cells by inducing apoptosis and other cell death pathways while sparing healthy differentiated cells [5]. Consequently, the calcium-binding site is a critical structural element that governs the protein's transition from a nutritional role to a potential anti-tumor therapeutic agent.
Formation of pro-apoptotic complexes; Induction of selective tumor cell death; Regulation of lactose synthesis.
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