Phosphatase Subfamily Synaptojanin

Phosphatase Classification: Fold CC1: Superfamily CC1: Family Sac: Subfamily Synaptojanin

Evolution

Synaptojanin is found throughout eukaryotes except excavate and some chromalveolate. Human has two members (SYNJ1/INPP5G and SYNJ2/INPP5H) which originated from a duplication event in tetrapods (internal data of gOrtholog database).

Domain

Synaptojanin has two domains, a CC1-fold phosphatase domain and a 5-phosphatase domain. Both domains are active. Synaptojanin also has a proline-rich region at C-terminal tail [1]., which binds to SH3 or WW domains of other proteins (e.g. endophilin and amphiphysin, EEN and Abi-1). The SH3 domains of different proteins bind to different sites of the proline-rich region [2, 3].

Function

Human SYNJ1 is mainly expressed in brain [4].

SYNJ1 binds to amphiphysin via SH3 domain of amphiphysin, which binds to dynamic directly via its SH3 domain. The three proteins form a stable complex in nerve terminals [5].

SYNJ1 is stably associated with endophilin in the nerve termina via SH3 domain of endophilin [5]. It is worthy pointing out that the SH3 domains of endophilin and amphiphysin bind to different sites of the proline-rich region of SYNJ1 [2].

Human SYNJ1 also interacts with other proteins such as GRB2 [4]. SYNJ1 (p170 isoform) binds to Eps15, a clathrin coat-associated protein, via its proline-rich region [6]. SYNJ1 binds to sorting nexin 9 (SNX9), a binding partner for the non-receptor and Cdc42-associated kinase (ACK), via its proline-rich region [7].

SYNJ1 is regulated by its phosphorylation state in the proline-rich region at C terminal. CDK5 phosphorylates SYNJ1 at serine-1144 which is close to the endophilin-binding site, which results in inhibiting the association of SYNJ1 and endophilin [8]. EphB2 phosphorylates SYNJ1 at tyrosine residues in the proline-rich region and inhibits both the interaction with endophilin and the 5'-phosphatase activity of SYNJ1 [9].

SYNJ1 variants are associated with Parkinsonism (a symptom complex that differs from Parkinson disease which is a progressive neurodegenerative illness) [10, 11, 12, 13] and bipolar disorder [14, 15].

References

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