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 [5]. The three proteins form a stable complex in nerve terminals [6].

SYNJ1 is stably associated with endophilin in the nerve termina via SH3 domain of endophilin [6]. 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, 7]. SYNJ1 (p170 isoform) binds to Eps15, a clathrin coat-associated protein, via its proline-rich region [8]. SYNJ1 binds to sorting nexin 9 (SNX9), a binding partner for the non-receptor and Cdc42-associated kinase (ACK), via its proline-rich region [9].

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 [10]. 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 [11].

SYNJ1 variants are associated with Parkinsonism (a symptom complex that differs from Parkinson disease which is a progressive neurodegenerative illness) [12, 13, 14, 15] and bipolar disorder [16, 17].

References

1. Zucconi A, Dente L, Santonico E, Castagnoli L, and Cesareni G. Selection of ligands by panning of domain libraries displayed on phage lambda reveals new potential partners of synaptojanin 1. J Mol Biol. 2001 Apr 13;307(5):1329-39. DOI:10.1006/jmbi.2001.4572 |
2. Cestra G, Castagnoli L, Dente L, Minenkova O, Petrelli A, Migone N, Hoffmüller U, Schneider-Mergener J, and Cesareni G. The SH3 domains of endophilin and amphiphysin bind to the proline-rich region of synaptojanin 1 at distinct sites that display an unconventional binding specificity. J Biol Chem. 1999 Nov 5;274(45):32001-7. DOI:10.1074/jbc.274.45.32001 |
3. So CW, So CK, Cheung N, Chew SL, Sham MH, and Chan LC. The interaction between EEN and Abi-1, two MLL fusion partners, and synaptojanin and dynamin: implications for leukaemogenesis. Leukemia. 2000 Apr;14(4):594-601. DOI:10.1038/sj.leu.2401692 |
4. McPherson PS, Takei K, Schmid SL, and De Camilli P. p145, a major Grb2-binding protein in brain, is co-localized with dynamin in nerve terminals where it undergoes activity-dependent dephosphorylation. J Biol Chem. 1994 Dec 2;269(48):30132-9.
5. McPherson PS, Garcia EP, Slepnev VI, David C, Zhang X, Grabs D, Sossin WS, Bauerfeind R, Nemoto Y, and De Camilli P. A presynaptic inositol-5-phosphatase. Nature. 1996 Jan 25;379(6563):353-7. DOI:10.1038/379353a0 |
6. Micheva KD, Kay BK, and McPherson PS. Synaptojanin forms two separate complexes in the nerve terminal. Interactions with endophilin and amphiphysin. J Biol Chem. 1997 Oct 24;272(43):27239-45. DOI:10.1074/jbc.272.43.27239 |
7. McPherson PS, Czernik AJ, Chilcote TJ, Onofri F, Benfenati F, Greengard P, Schlessinger J, and De Camilli P. Interaction of Grb2 via its Src homology 3 domains with synaptic proteins including synapsin I. Proc Natl Acad Sci U S A. 1994 Jul 5;91(14):6486-90. DOI:10.1073/pnas.91.14.6486 |
8. Haffner C, Takei K, Chen H, Ringstad N, Hudson A, Butler MH, Salcini AE, Di Fiore PP, and De Camilli P. Synaptojanin 1: localization on coated endocytic intermediates in nerve terminals and interaction of its 170 kDa isoform with Eps15. FEBS Lett. 1997 Dec 15;419(2-3):175-80. DOI:10.1016/s0014-5793(97)01451-8 |
9. Yeow-Fong L, Lim L, and Manser E. SNX9 as an adaptor for linking synaptojanin-1 to the Cdc42 effector ACK1. FEBS Lett. 2005 Sep 12;579(22):5040-8. DOI:10.1016/j.febslet.2005.07.093 |
10. Lee SY, Wenk MR, Kim Y, Nairn AC, and De Camilli P. Regulation of synaptojanin 1 by cyclin-dependent kinase 5 at synapses. Proc Natl Acad Sci U S A. 2004 Jan 13;101(2):546-51. DOI:10.1073/pnas.0307813100 |
11. Irie F, Okuno M, Pasquale EB, and Yamaguchi Y. EphrinB-EphB signalling regulates clathrin-mediated endocytosis through tyrosine phosphorylation of synaptojanin 1. Nat Cell Biol. 2005 May;7(5):501-9. DOI:10.1038/ncb1252 |
12. Krebs CE, Karkheiran S, Powell JC, Cao M, Makarov V, Darvish H, Di Paolo G, Walker RH, Shahidi GA, Buxbaum JD, De Camilli P, Yue Z, and Paisán-Ruiz C. The Sac1 domain of SYNJ1 identified mutated in a family with early-onset progressive Parkinsonism with generalized seizures. Hum Mutat. 2013 Sep;34(9):1200-7. DOI:10.1002/humu.22372 |
13. Quadri M, Fang M, Picillo M, Olgiati S, Breedveld GJ, Graafland J, Wu B, Xu F, Erro R, Amboni M, Pappatà S, Quarantelli M, Annesi G, Quattrone A, Chien HF, Barbosa ER, International Parkinsonism Genetics Network, Oostra BA, Barone P, Wang J, and Bonifati V. Mutation in the SYNJ1 gene associated with autosomal recessive, early-onset Parkinsonism. Hum Mutat. 2013 Sep;34(9):1208-15. DOI:10.1002/humu.22373 |
14. Picillo M, Ranieri A, Orefice G, Bonifati V, and Barone P. Clinical progression of SYNJ1-related early onset atypical parkinsonism: 3-year follow up of the original Italian family. J Neurol. 2014 Apr;261(4):823-4. DOI:10.1007/s00415-014-7270-6 |
15. Olgiati S, De Rosa A, Quadri M, Criscuolo C, Breedveld GJ, Picillo M, Pappatà S, Quarantelli M, Barone P, De Michele G, and Bonifati V. PARK20 caused by SYNJ1 homozygous Arg258Gln mutation in a new Italian family. Neurogenetics. 2014 Aug;15(3):183-8. DOI:10.1007/s10048-014-0406-0 |
16. Saito T, Guan F, Papolos DF, Lau S, Klein M, Fann CS, and Lachman HM. Mutation analysis of SYNJ1: a possible candidate gene for chromosome 21q22-linked bipolar disorder. Mol Psychiatry. 2001 Jul;6(4):387-95. DOI:10.1038/sj.mp.4000871 |
17. Stopkova P, Vevera J, Paclt I, Zukov I, and Lachman HM. Analysis of SYNJ1, a candidate gene for 21q22 linked bipolar disorder: a replication study. Psychiatry Res. 2004 Jun 30;127(1-2):157-61. DOI:10.1016/j.psychres.2004.03.003 |