Skip Header

You are using a version of browser that may not display all the features of this website. Please consider upgrading your browser.

UniProt release 2016_06

Published June 8, 2016


Strength through unity

Reversible phosphorylation of proteins is a fundamental regulatory mechanism for many processes across a wide range of taxa. It has been extensively studied in the context of intracellular events in the nucleus and in the cytoplasm. Less is known about extracellular phosphorylation, but a family of secretory pathway kinases has been identified within the Golgi apparatus and in the extracellular milieu in recent years. Among them, FAM20C has been shown to phosphorylate many secreted proteins involved in biomineralization, including enamel matrix proteins, such as AMBN, AMELX, AMTN and ENAM. The importance of extracellular phosphorylation in bone physiology is further supported by the observation that mutations in FAM20C are associated with Raine syndrome, an autosomal recessive osteosclerotic bone dysplasia with a neonatal lethal outcome.

FAM20A, FAM20C’s closest paralog, exhibits all characteristics of a kinase, except for one residue, a conserved glutamic acid residue which is replaced by a glutamine, causing a loss of enzyme activity. This is not a characteristic unique to FAM20A. About 10% of the proteins classified as protein kinases lack some of the key features required for activity. They are called “pseudokinases”. In spite of its lack of activity, mutations in FAM20A also produce a defect in biomineralization, namely amelogenesis imperfecta 1G.

This apparent paradox was solved by Cui et al. last year. They showed that in the absence of FAM20A, FAM20C activity dramatically drops. Moreover, FAM20A mutants associated with amelogenesis imperfecta 1G fail to activate FAM20C. The proteins have to form a complex for full FAM20C activity.

Kinases are synthesized as inactive proteins. Classically, their activation is achieved through the phosphorylation of a domain called the “activation loop” which induces a conformational change. FAM20C does not have an activation loop that could be phosphorylated. Yet another kind of activation, called “allosteric activation”, has already been reported for kinase-pseudokinase pairs. In this model, it is the pseudokinase binding that induces the shape change of the bona fide kinase into its active conformation. Although the exact mechanism of FAM20C activation is still unclear, experimental results suggest that it may join the growing list of kinases regulated by dimerization-induced allostery.

FAM20A and FAM20B are quite old enzymes, evolutionarily related to kinases found in bacteria and slime molds. The fact that they do not use activation loop phosphorylation suggests that the allosteric mode of kinase activation may be very ancient, before the activation loop evolved. The presence of many conserved pseudokinases in the genomes of higher organisms suggests that allosteric activation may still be an efficient regulatory mechanism.

As of this release, FAM20A and FAM20C have been updated and are publicly available.

UniProtKB news

Removal of the cross-references to NextBio

Cross-references to NextBio have been removed.

Changes to the controlled vocabulary of human diseases

New diseases:

Deleted diseases

  • Epilepsy, progressive myoclonic 5

RDF news

Change of URIs for neXtProt

For historic reasons, UniProt had to generate URIs to cross-reference databases that did not have an RDF representation. Our policy is to replace these by the URIs generated by the cross-referenced database once it starts to distribute an RDF representation of its data.

The URIs for the neXtProt database have therefore been updated from:<ID>


If required for backward compatibility, you can use the following query to add the old URIs:

PREFIX owl:<> 
PREFIX up:<> 
   ?protein rdfs:seeAlso ?old .
   ?old owl:sameAs ?new .
   ?old up:database <> .
   ?protein rdfs:seeAlso ?new .
   ?new up:database <> .
   BIND(iri(concat('', substr(str(?new),31))) AS ?old)

The dereferencing of existing<ID> URIs will be maintained.