Limits...
Modification by ubiquitin-like proteins: significance in apoptosis and autophagy pathways.

Cajee UF, Hull R, Ntwasa M - Int J Mol Sci (2012)

Bottom Line: Modifiers such as SUMO, ATG12, ISG15, FAT10, URM1, and UFM have been shown to modify proteins thus conferring functions related to programmed cell death, autophagy and regulation of the immune system.Putative modifiers such as Domain With No Name (DWNN) have been identified in recent times but not fully characterized.We review current progress in targeting these modifiers for drug design strategies.

View Article: PubMed Central - PubMed

Affiliation: School of Molecular & Cell Biology, Gatehouse 512, University of the Witwatersrand, Johannesburg, 2050, South Africa; E-Mails: umar.cajee@students.wits.ac.za (U.-F.C.); rodney.hull@students.wits.ac.za (R.H.).

ABSTRACT
Ubiquitin-like proteins (Ubls) confer diverse functions on their target proteins. The modified proteins are involved in various biological processes, including DNA replication, signal transduction, cell cycle control, embryogenesis, cytoskeletal regulation, metabolism, stress response, homeostasis and mRNA processing. Modifiers such as SUMO, ATG12, ISG15, FAT10, URM1, and UFM have been shown to modify proteins thus conferring functions related to programmed cell death, autophagy and regulation of the immune system. Putative modifiers such as Domain With No Name (DWNN) have been identified in recent times but not fully characterized. In this review, we focus on cellular processes involving human Ubls and their targets. We review current progress in targeting these modifiers for drug design strategies.

Show MeSH
Phylogenetic analysis of proteins with DWNN domains. Full RBBP6 orthologous protein sequences were aligned in MEGA 5, using the default ClustalW algorithm. The multiple sequence alignment was then analyzed and tweaked manually to ensure important conserved residues (lysines, di-glycine motif) were accurately aligned.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
getmorefigures.php?uid=PMC3472776&req=5

f3-ijms-13-11804: Phylogenetic analysis of proteins with DWNN domains. Full RBBP6 orthologous protein sequences were aligned in MEGA 5, using the default ClustalW algorithm. The multiple sequence alignment was then analyzed and tweaked manually to ensure important conserved residues (lysines, di-glycine motif) were accurately aligned.

Mentions: In plants, invertebrates and vertebrates RBBP6 proteins have a multi-domain arrangement with combinations of the p53- and Rb-binding, and SR domains in addition to the core ubiquitin-like domain that is linked to a zinc knuckle and RING finger (Figure 3) [104,105]. With the exception of vertebrate orthologues, DWNN lacks the characteristic C-terminal diglycine motif required for conjugation of ubiquitin and Ubls to substrates. The significance of this is not yet clear. These proteins are associated with cell- and tissue-specific cell proliferation, apoptosis and mRNA splicing. In some experiments using mice RBBP6 proteins have been shown to enhance the activity of Mdm2 (mouse double mutant). Interestingly, Rbbp6 and mdm2 mice also have a similar phenotype. The loss of RBBP6 has an embryonic lethal phenotype while double mutants of Rbbp6 and p53 develop better [106]. This phenotype is similar to that of mdm2−/−/p53−/− [107]. Taken together, these observations point to a close association between the function of Mdm2 and RBBP6. Although DWNN was identified earlier than UFM1, very little is known about the enzymology of conjugation. Indeed it is not known whether this domain can be conjugated to other proteins in the ubiquitin-like fashion. The existence of the mammalian DWNN domain as an independent module, however, points to this possibility.


Modification by ubiquitin-like proteins: significance in apoptosis and autophagy pathways.

Cajee UF, Hull R, Ntwasa M - Int J Mol Sci (2012)

Phylogenetic analysis of proteins with DWNN domains. Full RBBP6 orthologous protein sequences were aligned in MEGA 5, using the default ClustalW algorithm. The multiple sequence alignment was then analyzed and tweaked manually to ensure important conserved residues (lysines, di-glycine motif) were accurately aligned.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC3472776&req=5

f3-ijms-13-11804: Phylogenetic analysis of proteins with DWNN domains. Full RBBP6 orthologous protein sequences were aligned in MEGA 5, using the default ClustalW algorithm. The multiple sequence alignment was then analyzed and tweaked manually to ensure important conserved residues (lysines, di-glycine motif) were accurately aligned.
Mentions: In plants, invertebrates and vertebrates RBBP6 proteins have a multi-domain arrangement with combinations of the p53- and Rb-binding, and SR domains in addition to the core ubiquitin-like domain that is linked to a zinc knuckle and RING finger (Figure 3) [104,105]. With the exception of vertebrate orthologues, DWNN lacks the characteristic C-terminal diglycine motif required for conjugation of ubiquitin and Ubls to substrates. The significance of this is not yet clear. These proteins are associated with cell- and tissue-specific cell proliferation, apoptosis and mRNA splicing. In some experiments using mice RBBP6 proteins have been shown to enhance the activity of Mdm2 (mouse double mutant). Interestingly, Rbbp6 and mdm2 mice also have a similar phenotype. The loss of RBBP6 has an embryonic lethal phenotype while double mutants of Rbbp6 and p53 develop better [106]. This phenotype is similar to that of mdm2−/−/p53−/− [107]. Taken together, these observations point to a close association between the function of Mdm2 and RBBP6. Although DWNN was identified earlier than UFM1, very little is known about the enzymology of conjugation. Indeed it is not known whether this domain can be conjugated to other proteins in the ubiquitin-like fashion. The existence of the mammalian DWNN domain as an independent module, however, points to this possibility.

Bottom Line: Modifiers such as SUMO, ATG12, ISG15, FAT10, URM1, and UFM have been shown to modify proteins thus conferring functions related to programmed cell death, autophagy and regulation of the immune system.Putative modifiers such as Domain With No Name (DWNN) have been identified in recent times but not fully characterized.We review current progress in targeting these modifiers for drug design strategies.

View Article: PubMed Central - PubMed

Affiliation: School of Molecular & Cell Biology, Gatehouse 512, University of the Witwatersrand, Johannesburg, 2050, South Africa; E-Mails: umar.cajee@students.wits.ac.za (U.-F.C.); rodney.hull@students.wits.ac.za (R.H.).

ABSTRACT
Ubiquitin-like proteins (Ubls) confer diverse functions on their target proteins. The modified proteins are involved in various biological processes, including DNA replication, signal transduction, cell cycle control, embryogenesis, cytoskeletal regulation, metabolism, stress response, homeostasis and mRNA processing. Modifiers such as SUMO, ATG12, ISG15, FAT10, URM1, and UFM have been shown to modify proteins thus conferring functions related to programmed cell death, autophagy and regulation of the immune system. Putative modifiers such as Domain With No Name (DWNN) have been identified in recent times but not fully characterized. In this review, we focus on cellular processes involving human Ubls and their targets. We review current progress in targeting these modifiers for drug design strategies.

Show MeSH