Phosphorylation Mechanisms in Biomineralization Disorders

Biomineralization disorders arise when the tightly regulated process of depositing mineral phases in tissues becomes disrupted. Central to this regulation is protein phosphorylation, a reversible post-translational modification that alters protein activity, localisation and interactions. Secretory pathway kinases, in particular the Fam20 family, phosphorylate matrix proteins and proteoglycans in the Golgi and extracellular milieu. Through these actions they govern nucleation, crystal growth and inhibition of ectopic mineral deposition in bone, dentine and enamel. Genetic defects in these kinases or their regulators lead to syndromes characterised by hypomineralisation or pathological calcifications, such as Raine syndrome, amelogenesis imperfecta and nephrocalcinosis. Deciphering the structural basis of kinase activation, substrate specificity and downstream signalling networks has yielded insights into phosphate homeostasis, extracellular matrix assembly and potential therapeutic targets for skeletal and dental pathologies.

Research from Nature Portfolio

Structural and evolutionary analyses have revealed that a family of secretory pathway kinases diversifies function through changes in oligomeric state and active-site architecture. One foundational study showed that the prototypical kinase exists as a homodimer or a heterodimer with a non-catalytic paralogue, which allosterically modulates substrate recognition and imposes specificity for both proteoglycan linkers and phosphoproteins. A complementary investigation demonstrated that the non-enzymatic partner governs the extracellular localisation of the catalytic kinase, with loss of this regulator preventing secretion of the active enzyme and abrogating mineral deposition in cell-based assays. Together, these works establish a mechanistic framework linking kinase assembly, substrate phosphorylation and the extracellular matrix changes essential for normal mineralisation.

Phosphorylation Mechanisms in Biomineralization Disorders publication trend

The graph below shows the total number of articles in phosphorylation mechanisms in biomineralization disorders across all publications each year (not limited to Nature Index journals).

Technical terms

Phosphorylation: The enzymatic addition of a phosphate group to a protein, modulating its function or interactions.

Kinase: An enzyme that catalyses the transfer of a phosphate group, typically from ATP, to a substrate protein.

Pseudokinase: A kinase-like protein lacking catalytic activity but capable of regulatory interactions with active kinases.

Biomineralization: The biological process by which organisms produce mineralised tissues such as bone, dentine and enamel.

SIBLING proteins: A family of small integrin-binding glycoproteins present in the extracellular matrix that regulate mineralisation.

References

1. Structure and evolution of the Fam20 kinases. Nature Communications (2018).
2. A secretory kinase complex regulates extracellular protein phosphorylation. eLife (2015).
3. FAM20A binds to and regulates FAM20C localization. Scientific Reports (2016).
4. The ABCs of the atypical Fam20 secretory pathway kinases. Journal of Biological Chemistry (2021).
5. Fam20c regulates the calpain proteolysis system through phosphorylating Calpasatatin to maintain cell homeostasis. Journal of Translational Medicine (2023).
6. The Raine Syndrome Protein FAM20C Is a Golgi Kinase That Phosphorylates Bio-Mineralization Proteins. PLOS ONE (2012).