The GAFa Domain of Phosphodiesterase-6 Contains a Rod Outer Segment Localization Signal

Overview

Journal J Neurochem

Specialties Chemistry
Neurology

Date 2013 Oct 24

PMID 24147783

Citations 6

Authors

Pallavi Cheguru

Zhongming Zhang

Nikolai O Artemyev

Affiliations

Soon will be listed here.

Abstract

Photoreceptor phosphodiesterase-6 (PDE6) is a peripheral membrane protein synthesized in the inner segment of photoreceptor cells. Newly synthesized PDE6 is transported to the outer segment (OS) where it serves as a key effector enzyme in the phototransduction cascade. Proper localization of PDE6 in photoreceptors is critically important to the function and survival of photoreceptor cells. The mechanism of PDE6 transport to the OS remains largely unknown. In this study, we investigated potential OS targeting signals of PDE6 by constructing cGMP-binding, cGMP-specific phosphodiesterase-5/PDE6 chimeric proteins and analyzing their localization in rods of transgenic Xenopus laevis. We found that efficient OS localization of chimeric isoprenylated PDE enzymes required the presence of a targeting motif within the PDE6 GAFa domain. Furthermore, the GAFa-dependent localization signal was sufficient to target GAFa fusion protein to the OS. Our results support the idea that effective trafficking of the peripheral membrane proteins to the OS of photoreceptor cells requires a sorting/targeting motif in addition to a membrane-binding signal.

Citing Articles

Photoreceptor phosphodiesterase (PDE6): activation and inactivation mechanisms during visual transduction in rods and cones.

Cote R Pflugers Arch. 2021; 473(9):1377-1391.

PMID: 33860373 PMC: 8376765. DOI: 10.1007/s00424-021-02562-x.

The ubiquitin-like modifier FAT10 inhibits retinal PDE6 activity and mediates its proteasomal degradation.

Boehm A, Bialas J, Catone N, Sacristan-Reviriego A, van der Spuy J, Groettrup M J Biol Chem. 2020; 295(42):14402-14418.

PMID: 32817338 PMC: 7573256. DOI: 10.1074/jbc.RA120.013873.

The PDE6 mutation in the rd10 retinal degeneration mouse model causes protein mislocalization and instability and promotes cell death through increased ion influx.

Wang T, Reingruber J, Woodruff M, Majumder A, Camarena A, Artemyev N J Biol Chem. 2018; 293(40):15332-15346.

PMID: 30126843 PMC: 6177582. DOI: 10.1074/jbc.RA118.004459.

Mechanisms of mutant PDE6 proteins underlying retinal diseases.

Gopalakrishna K, Boyd K, Artemyev N Cell Signal. 2017; 37:74-80.

PMID: 28583373 PMC: 5554458. DOI: 10.1016/j.cellsig.2017.06.002.

Distinct patterns of compartmentalization and proteolytic stability of PDE6C mutants linked to achromatopsia.

Cheguru P, Majumder A, Artemyev N Mol Cell Neurosci. 2014; 64:1-8.

PMID: 25461672 PMC: 4323879. DOI: 10.1016/j.mcn.2014.10.007.

References

Gelb M, Brunsveld L, Hrycyna C, Michaelis S, Tamanoi F, Van Voorhis W . Therapeutic intervention based on protein prenylation and associated modifications. Nat Chem Biol. 2006; 2(10):518-28. PMC: 2892741. DOI: 10.1038/nchembio818. View

Kerov V, Rubin W, Natochin M, Melling N, Burns M, Artemyev N . N-terminal fatty acylation of transducin profoundly influences its localization and the kinetics of photoresponse in rods. J Neurosci. 2007; 27(38):10270-7. PMC: 6672661. DOI: 10.1523/JNEUROSCI.2494-07.2007. View

Artemyev N, Natochin M, Busman M, Schey K, Hamm H . Mechanism of photoreceptor cGMP phosphodiesterase inhibition by its gamma-subunits. Proc Natl Acad Sci U S A. 1996; 93(11):5407-12. PMC: 39259. DOI: 10.1073/pnas.93.11.5407. View

Ramamurthy V, Niemi G, Reh T, Hurley J . Leber congenital amaurosis linked to AIPL1: a mouse model reveals destabilization of cGMP phosphodiesterase. Proc Natl Acad Sci U S A. 2004; 101(38):13897-902. PMC: 518850. DOI: 10.1073/pnas.0404197101. View

Muradov H, Boyd K, Artemyev N . Rod phosphodiesterase-6 PDE6A and PDE6B subunits are enzymatically equivalent. J Biol Chem. 2010; 285(51):39828-34. PMC: 3000964. DOI: 10.1074/jbc.M110.170068. View

Tsang S, Gouras P, Yamashita C, Kjeldbye H, Fisher J, Farber D . Retinal degeneration in mice lacking the gamma subunit of the rod cGMP phosphodiesterase. Science. 1996; 272(5264):1026-9. PMC: 2757426. DOI: 10.1126/science.272.5264.1026. View

Muradov K, Granovsky A, Schey K, Artemyev N . Direct interaction of the inhibitory gamma-subunit of Rod cGMP phosphodiesterase (PDE6) with the PDE6 GAFa domains. Biochemistry. 2002; 41(12):3884-90. DOI: 10.1021/bi015935m. View

Pearring J, Salinas R, Baker S, Arshavsky V . Protein sorting, targeting and trafficking in photoreceptor cells. Prog Retin Eye Res. 2013; 36:24-51. PMC: 3759535. DOI: 10.1016/j.preteyeres.2013.03.002. View

Malinski J, Wensel T . Membrane stimulation of cGMP phosphodiesterase activation by transducin: comparison of phospholipid bilayers to rod outer segment membranes. Biochemistry. 1992; 31(39):9502-12. DOI: 10.1021/bi00154a024. View

10.

Azadi S, Molday L, Molday R . RD3, the protein associated with Leber congenital amaurosis type 12, is required for guanylate cyclase trafficking in photoreceptor cells. Proc Natl Acad Sci U S A. 2010; 107(49):21158-63. PMC: 3000275. DOI: 10.1073/pnas.1010460107. View

11.

Deretic D, Wang J . Molecular assemblies that control rhodopsin transport to the cilia. Vision Res. 2012; 75:5-10. PMC: 3514645. DOI: 10.1016/j.visres.2012.07.015. View

12.

Zhang F, Casey P . Protein prenylation: molecular mechanisms and functional consequences. Annu Rev Biochem. 1996; 65:241-69. DOI: 10.1146/annurev.bi.65.070196.001325. View

13.

Karan S, Frederick J, Baehr W . Novel functions of photoreceptor guanylate cyclases revealed by targeted deletion. Mol Cell Biochem. 2009; 334(1-2):141-55. PMC: 2832916. DOI: 10.1007/s11010-009-0322-z. View

14.

Karan S, Tam B, Moritz O, Baehr W . Targeting of mouse guanylate cyclase 1 (Gucy2e) to Xenopus laevis rod outer segments. Vision Res. 2011; 51(21-22):2304-11. PMC: 3205228. DOI: 10.1016/j.visres.2011.09.001. View

15.

Kroll K, Amaya E . Transgenic Xenopus embryos from sperm nuclear transplantations reveal FGF signaling requirements during gastrulation. Development. 1996; 122(10):3173-83. DOI: 10.1242/dev.122.10.3173. View

16.

Hagstrom S, Watson R, Pauer G, Grossman G . Tulp1 is involved in specific photoreceptor protein transport pathways. Adv Exp Med Biol. 2011; 723:783-9. DOI: 10.1007/978-1-4614-0631-0_100. View

17.

Conti M, Beavo J . Biochemistry and physiology of cyclic nucleotide phosphodiesterases: essential components in cyclic nucleotide signaling. Annu Rev Biochem. 2007; 76:481-511. DOI: 10.1146/annurev.biochem.76.060305.150444. View

18.

Tam B, Moritz O, Papermaster D . The C terminus of peripherin/rds participates in rod outer segment targeting and alignment of disk incisures. Mol Biol Cell. 2004; 15(4):2027-37. PMC: 379296. DOI: 10.1091/mbc.e03-09-0650. View

19.

Zhang Z, Artemyev N . Determinants for phosphodiesterase 6 inhibition by its gamma-subunit. Biochemistry. 2010; 49(18):3862-7. PMC: 2864356. DOI: 10.1021/bi100354a. View

20.

Pittler S, Baehr W . Identification of a nonsense mutation in the rod photoreceptor cGMP phosphodiesterase beta-subunit gene of the rd mouse. Proc Natl Acad Sci U S A. 1991; 88(19):8322-6. PMC: 52500. DOI: 10.1073/pnas.88.19.8322. View