Phosphatase Subfamily Synaptojanin

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

Synaptojanin is a PtdIns(3,5)P2 phosphatase in the endocytic pathway. It has two phosphatase domains dephosphorylate 3-position and 5-position of PtdIns(3,5)P2, respectively. It 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.

Evolution

Synaptojanin is found throughout eukaryotes except excavate and some chromalveolates. 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 Sac phosphatase domain and a 5-phosphatase domain. Both domains are active, which dephosphorylate 3' and 5' positions of phosphatidylinositol(4,5)bisphosphate (PI(4,5)P2), respectively. This domain combination enables synaptojanin to hydrolyse PI(4,5)P2 to PI without producing another signal, PI4P [1]. The Sac phosphatase domain also mediates the targeting of synaptojanin to synapses [2].

Synaptojanin also has a proline-rich region at C-terminal tail [3]., 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 [4, 5].

Function

The two human synaptojanins SYNJ1 and SYNJ2 have distinct functions.

Human SYNJ1

Human SYNJ1 is mainly expressed in brain [6]. SYNJ1 mRNA was detected in almost all neurons of the central nervous system throughout developing and mature stages, and its splicing variant p140 mRNA was expressed dominantly in forebrain and cerebellar cortex [7]. According to GTEx data, SYNJ1 is widely expressed in diverse tissues and most abundantly expressed in brain. But, in contrast with SYNJ2, it is not expressed at high level in spinal cord.

It functions in endocytosis (particularly, vesicle uncoating) in neurons. It interacts with other proteins involved in vesicle uncoating:

• Amphiphysin. SYNJ1 binds to amphiphysin via SH3 domain of amphiphysin, which binds to dynamin directly via its SH3 domain [8]. The three proteins form a stable complex in nerve terminals [9].
• Endophilin. SYNJ1 is stably associated with endophilin in the nerve termina via SH3 domain of endophilin [9]. It is worthy pointing out that the SH3 domains of endophilin and amphiphysin bind to different sites of the proline-rich region of SYNJ1 [4].
• GRB2. SYNJ1 also interacts with other proteins such as GRB2 via SH3 domain [6, 10].
• Eps15, a clathrin coat-associated protein. SYNJ1 (p170 isoform) binds to Eps15 via its proline-rich region [11].
• SNX9, Sorting nexin 9, a binding partner for the non-receptor and Cdc42-associated kinase (ACK). SYNJ1 binds to SNX9 via its proline-rich region [12].

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 [13]. 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 [14].

SYNJ1 variants are associated with Parkinsonism (a symptom complex that differs from Parkinson disease which is a progressive neurodegenerative illness) [15, 16, 17, 18] and bipolar disorder [19, 20]. Reduction of SYNJ1 accelerates Aβ clearance and attenuates cognitive deterioration in an Alzheimer mouse model [21].

Human SYNJ2

SNYJ2 mRNA was first detected in neurons of the olfactory bulb, the cerebral cortex, the hippocampus, and the cerebellar cortex on early postnatal days [7]. According to GTEx data, SYNJ2 is widely expressed in diverse tissues and most abundantly expressed in brain, especially in spinal cord. In contrast, SYNJ1 is expressed in a relative low level in spinal cord compared with other parts of brain.

SYNJ2 functions in endocytosis as well as SYNJ1. However, it is involved in clathrin-mediated receptor internalization, an early step of endocytosis; in contrast, SYNJ1 is involved in vesicle uncoating, a late step of endocytosis [22].

SYNJ2 has at least three different isoforms, SYNJ2A, SYNJ2B1, SYNJ2B2. The isoforms have different though overlapping interacting partners. This is supported by the sequence differences of SYNJ1 and different isoforms SYNJ2 in their proline-rich regions [23, 24, 25].

SYNJ2 regulates clathrin-mediated endocytosis as the effector of the small GTPase Rac [26, 27]. Active RAC1 affects the intracellular localization of SYNJ2, but not of SYNJ1 [25].

SYNJ2 is phosphorylated and activated by Src through the phosphorylation of Tyr-490 in vitro [28]. Tyr-490 locates in the linker between two phosphatase domains.

SYNJ2 is recognized by HLA class II-restricted hairy cell leukemia-specific T cells [29].

References

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