Effect on the Ras/Raf signaling pathway of post-translational modifications of neurofibromin: in silico study of protein modification responsible for regulatory pathways.
Mapping and chemical characterization of post-translational modifications (PTMs) in proteins are critical to understand the regulatory mechanisms involving modified proteins and their role in disease. Neurofibromatosis type 1 (NF-1) is an autosomal dominantly inherited disorder, where NF1 mutations usually result in a reduced level of the tumor suppressor protein, neurofibromin (NF). NF is a multifunctional cytoplasmic protein that regulates microtubule dynamics and participates in several signaling pathways, particularly the RAS signaling pathway. NF is a Ras GTPase-activating protein (GAP) that prevents oncogenesis by converting GTP-Ras to GDP-Ras. This function of NF is regulated by phosphorylation. Interplay of phosphorylation with O-GlcNAc modification on the same or vicinal Ser/Thr residues, the Yin Yang sites, is well known in cytoplasmic and nuclear proteins. The dynamic aspects of PTMs and their interplay being difficult to follow in vivo, we undertook this in silico work to predict and define the possible role of Yin Yang sites in NF-1. Interplay of phosphorylation and O-GlcNAc modification is proposed as a mechanism controlling the Ras signaling pathway.
Institute of Molecular Sciences and Bioinformatics, Lahore, Pakistan. professor_nasir@yahoo.com
Kaleem
Afshan
A
Ahmad
Ishtiaq
I
Walker-Nasir
Evelyne
E
Hoessli
Daniel C
DC
Shakoori
Abdul Rauf
AR
D000117:Acetylglucosamine / Q000737:chemistry; D000595:Amino Acid Sequence; D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism; D020690:GTPase-Activating Proteins / Q000737:chemistry; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D025542:Neurofibromin 1 / Q000737:chemistry*; D010766:Phosphorylation; D011485:Protein Binding; D011499:Protein Processing, Post-Translational; D017434:Protein Structure, Tertiary; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D048490:raf Kinases / Q000378:metabolism*; D018631:ras Proteins / Q000378:metabolism*
D020690:GTPase-Activating Proteins; D025542:Neurofibromin 1; D048490:raf Kinases; D018631:ras Proteins; D000117:Acetylglucosamine