Are casein micelles extracellular condensates formed by liquid‐liquid phase separation?

• Published in: FEBS letters Vol. 596; no. 16; pp. 2072 - 2085
• Main Authors: Horvath, Attila, Fuxreiter, Monika, Vendruscolo, Michele, Holt, Carl, Carver, John A.
• Format: Journal Article
• Language: English
• Published: 01.08.2022
• Subjects: biomolecular condensate; calcium phosphates; casein; casein micelle; liquid–liquid phase separation; micelles; milk; molecular chaperone; multivalent interactions; nanocluster; nanoparticles; protein aggregation; separation
• ISSN: 0014-5793; 1873-3468; 1873-3468
• DOI: 10.1002/1873-3468.14449

Casein micelles are extracellular polydisperse assemblies of unstructured casein proteins. Caseins are the major component of milk. Within casein micelles, casein molecules are stabilised by binding to calcium phosphate nanoclusters and, by acting as molecular chaperones, through multivalent interactions. In the light of such interactions, we discuss whether casein micelles can be considered as extracellular condensates formed by liquid–liquid phase separation. We analyse the sequence, structure and interactions of caseins in comparison with proteins forming intracellular condensates. Furthermore, we review the similarities between caseins and small heat‐shock proteins whose chaperone activity is linked to phase separation of proteins. By bringing these observations together, we describe a regulatory mechanism for protein condensates, as exemplified by casein micelles. Casein proteins are the major components of milk, where they form large, polydisperse assemblies known as casein micelles. Within these extracellular casein micelles, caseins are stabilised by binding to calcium phosphate nanoclusters and through multivalent interactions. Here, we propose that these interactions are similar to those associated with liquid–liquid phase separation in intracellular biomolecular condensates such as membraneless organelles.