Scientific Newsletter Logo Retina International's

Scientific Newsletter


The Protein Pages
Control by Modification of Proteins

Recent update from: 12.06.00

As reported by Sung et al. (11), (9), (10) mutations in the rhodopsin gene causing adRP can be divided into two groups as to their behaviour in human cell cultures. The first group behaves wild type like concerning chromophore binding and accumulation in the plasma membrane. The second group leads to accumulation of rhodopsin in the ER, does not bind the chromophore, or has defect insertion of rhodopsin into the cell membrane. In part this is due to mutations exchanging posttranslational modified amino acids with glycosylation or fatty acid modifications.

While glycosylation patterns are necessary for intracellular trafficking and chromophore binding, fatty acid modifications are essential for membrane binding and orientation. Therefore, proteins introducing modifications to nascent proteins are important for optimal function and stable insertion of membrane associated proteins.

Further, protein activity and interactions are regulated by phosphorylation. Phosphorylation and phosphorylated proteins of the visual cascade are summarized on our page on "Regulation of the Visual Cascade".

Together with rhodopsin carrying two palmitoyl residues at Cys321/322 (6) GCAP , RHOK , RCV, GNG, PDEA , and PDEB are fatty acid modified at the C-terminus (1), (3), (5), (4). While PDEB is geranylated, RHOK , GNG , and PDEA are farnesylated.

Geranylgeranyl- and farnesyl-modifications are introduced by watersoluble prenyl transferase. Two, that modify Carboxyterminal cysteine residues by geranylgeranyl groups (GGTaseI and GGTaseII or Rab GGTase) and one which farnesylated Carboxyterminal cysteine (FTase) . All prenyl transferase require Zn2+ for catalytic activity (2). The catalytic subunits are Mg2+ dependent to recognize the Diphosphate-moiety of the transferred prenyl-group (7).

GGTaseI and FTase share a common a-subunit and have a substrate specific b-subunit (12). Both recognize an identical C-terminal sequence motif (CAAX = Cys-aliphatic-aliphatic-transferase specific). The C-terminal amino acid recognized by GGTaseI is leucine, while FTase recognizes their substrate by C-termini of methionine or serine residues (2).

In contrast to GGTaseI and FTase , GGTaseII is a trimeric enzyme which requires a third subunit, a substrate carrier, for activity. GGTaseII is highly substrate specific since it modifies only members of the Rab-protein family (2) Which are required for intracellular trafficking of cellular vesicles. Therefore, GGTaseII is termed Rab GGTase .
Rab GGTase subunits are different from GGTaseI and FTase (7) but share homologies in the catalytic subunits with the other two prenyl transferase
As mentioned before Rab GGTase requires a substrate carrier, termed Rab Escort Protein for catalytic activity. The substrate carrier recognizes and delivers the Rab proteins to geranylation. Unlike the substrates of GGTaseI and FTase Rab proteins are not only recognized by their C-terminal residues but additionally require recognition of a yet not identified sequence inside the protein (8) . Rab protein C-termini end in CC or CXC (Cys-Cys or Cys-any amino acid-Cys). Both cysteines can be geranylated (2).

References
  1. Anant,J.S., Ong,O.C., Xie,H., Clarke,S., Obrien,P.J., Fung,B.K.K., Xie,H.Y., O'Brien,P.J., and Fung,B.K. Invivo Differential Prenylation of Retinal Cyclic GMP Phosphodiesterase Catalytic Subunits. 1992; J.Biol.Chem. 267: 687-690.
    Link to PubMed
    Goto Top

  2. Casey,P.J., Moomaw,J.F., Zhang,F.L., Higgins,J.B., and Thissen,J.A. Prenylation and G protein signaling. 1994; Recent.Prog.Horm.Res. 49: 215-238.
    Goto Top

  3. Cotlier,E., Morris,G.N., and Pullarkat,R.K. A prenylated protein defect in Bardet-Biedl syndrome. 1994; Invest.Ophthalmol.Vis.Sci. 35 (Suppl.): 1717
    Goto Top

  4. Demar,J.C., Wensel,T.G., and Anderson,R.E. Metabolic pathways for the generation of the unsaturated C-14 fatty acids found on the N-terminus of transducin. 1995; Invest.Ophthalmol.Vis.Sci. 36: S223
    Goto Top

  5. Dizhoor,A.M., Ericsson,L.H., Johnson,R.S., Kumar,S., Olshevskaya,E., Zozulya,S., Neubert,T.A., Stryer,L., Hurley,J.B., and Walsh,K.A. The NH2 terminus of retinal recoverin is acylated by a small family of fatty acids. 1992; J.Biol.Chem. 267: 16033-16036.
    Link to PubMed
    Goto Top

  6. Hargrave,P.A. and McDowell,J.H. Rhodopsin and phototransduction: a model system for G protein- linked receptors. 1992; FASEB Journal. 6: 2323-2331.
    Link to PubMed
    Goto Top

  7. Sanders,R., Islam,K.B., Betz,R., Larsson,C., and Smith,C.I. A human homologue of the rat rab geranylgeranyl transferase beta subunit on chromosome 1p22-p31. 1996; Genomics. 35: 633-635.
    Goto Top

  8. Seabra,M.C., Goldstein,J.L., Sudhof,T.C., and Brown,M.S. Rab geranylgeranyl transferase. A multisubunit enzyme that prenylates GTP-binding proteins terminating in Cys-X-Cys or Cys- Cys. 1992; J.Biol.Chem. 267: 14497-14503.
    Link to PubMed
    Goto Top

  9. Sung,C.H., Davenport,C.M., Hennessey,J.C., Maumenee,I.H., Jacobson,S.G., Heckenlively,J.R., Nowakowski,R., Fishman,G., Gouras,P., and Nathans,J. Rhodopsin mutations in autosomal dominant retinitis pigmentosa Rhodopsin mutations in autosomal dominant retinitis pigmentosa. 1991; Proc.Natl.Acad.Sci.U.S.A. 88: 6481-6485.
    Link to PubMed
    Goto Top

  10. Sung,C.H., Davenport,C.M., and Nathans,J. Rhodopsin mutations responsible for autosomal dominant retinitis pigmentosa. Clustering of functional classes along the polypeptide chain. 1993; J.Biol.Chem. 268: 26645-26649.
    Link to PubMed
    Goto Top

  11. Sung,C.H., Schneider,B.G., Agarwal,N., Papermaster,D.S., and Nathans,J. Functional heterogeneity of mutant rhodopsins responsible for autosomal dominant retinitis pigmentosa. 1991; Proc.Natl.Acad.Sci.U.S.A. 88: 8840-8844.
    Link to PubMed
    Goto Top

  12. Zhang,F.L., Diehl,R.E., Kohl,N.E., Gibbs,J.B., Giros,B., Casey,P.J., and Omer,C.A. cDNA cloning and expression of rat and human protein geranylgeranyltransferase type-I. 1994; J.Biol.Chem. 269: 3175-3180.
    Link to PubMed
    Goto Top
Return to Retina International's
Scientific Newsletter 		Return to pagehead

Contact the editor 		This site is maintained and edited by
Dr. rer. medic. Markus Preising, Dipl.Biol.
Molecular Genetics Laboratory
Department of Paediatric Ophthalmology, Strabismology and Ophthalmogenetics
University of Regensburg
Head: Prof. Dr. med. Birgit Lorenz