Casein micelle structure: What can be learned from milk synthesis and structural biology? H.M. Farrell Jr. ⁎ , E.L. Malin, E.M. Brown, P.X. Qi USDA, ARS, ERRC, 600 E. Mermaid Lane, Wyndmoor, PA 19038, USA Available online 8 February 2006 Abstract At the heart of the skim milk system are the colloidal casein–calcium–transport complexes termed the casein micelles. The application of physical chemical techniques such as light, neutron, and X-ray scattering and electron microscopy has yielded a wealth of experimental detail concerning the structure of the casein micelle. From these experimental data bases have arisen two conflicting models for the internal structure of the casein micelle. One model emphasizes protein submicellar structures as the dominant feature, while the other proposes that inorganic calcium phosphate nanoclusters serve this function. These models are critically examined in light of our current information regarding the biological processes of protein secretion. In addition two primary tenets of structural biology are applied: that protein structure gives rise to function and that competent protein–protein interactions (associations) will lead to efficient transit through the mammary secretory apparatus. However, a set of complex equilibria governs this process which may be completed only after the final step in the processes: milking. In this light an overwhelming argument can be made for the formation of proteinacious complexes (submicelles) as the formative agents in the synthesis of casein micelles in mammary tissue. Whether these submicelles persist in the milk has been questioned. However, perturbations in micellar equilibria allow for the reemergence of submicellar particles in dairy products such as cheese. Thus protein–protein interactions appear to be important in milk and dairy products from the endoplasmic reticulum to the cheese cutting board. Published by Elsevier Ltd. 1. Introduction The virtual image of milk, which would be constructed by most people, is that of a creamy white fluid. The lubricity and taste of milk are related to this perception and are based upon three unique biological structures: the colloidal calcium–protein complexes (the casein micelles), the milk fat globules with their limiting membrane, and the milk sugar: lactose [1 •• ]. The complexity of these structures is necessitated by the fact that milk is in essence predominantly water. It is the accommodation of these ingredients to an aqueous environment that forms the basis for the structure of milk at the molecular level and calls for the unique secretory process: milk synthesis [1 •• ]. This review will center on the colloidal calcium–phosphate complexes of skim milk—the casein micelles. These colloids have been the subject of research for many years [2 •• –4]. Biochemical and physical studies of these colloids have focused on: the size and properties of the colloids, their protein and mineral composition, and stepwise reconstitution of the micelles. Conflicting models for the structure of the casein micelles have arisen from differing interpretations of the core data bases developed in these studies. It is the intent of this manuscript to examine these models in terms of the biological processes noted above. In addition the principles of the field of structural biology will be applied to attempt to discern the biologically competent route for the formation of the casein micelles. These thoughts may help clarify the disparate models for the most important feature of the skim milk system—the casein micelles. 1.1. Gross composition of milk The composition of milk varies widely across species, with stage of lactation, and in response to diet. For the sake of comparison, the compositions of goat, cow and human milks [5] will be presented since they are well studied and of nutritional and commercial importance to most readers. The total solids contents of the three milks are roughly the same Current Opinion in Colloid & Interface Science 11 (2006) 135 – 147 www.elsevier.com/locate/cocis ⁎ Corresponding author. Tel.: +1 215 659 6410; fax: +1 215 233 6559. E-mail address: hfarrell@errc.ars.usda.gov (H.M. Farrell). 1359-0294/$ - see front matter. Published by Elsevier Ltd. doi:10.1016/j.cocis.2005.11.005