5uhv | pdb_00005uhv
wild-type NRas bound to GppNHp
Structural highlights
Disease[RASN_HUMAN] Defects in NRAS are a cause of juvenile myelomonocytic leukemia (JMML) [MIM:607785]. JMML is a pediatric myelodysplastic syndrome that constitutes approximately 30% of childhood cases of myelodysplastic syndrome (MDS) and 2% of leukemia. Defects in NRAS are the cause of Noonan syndrome type 6 (NS6) [MIM:613224]. A syndrome characterized by facial dysmorphic features such as hypertelorism, a downward eyeslant and low-set posteriorly rotated ears. Other features can include short stature, a short neck with webbing or redundancy of skin, cardiac anomalies, deafness, motor delay and variable intellectual deficits.[1] Defects in NRAS are the cause of autoimmune lymphoproliferative syndrome type 4 (ALPS4) [MIM:614470]. A disorder of apoptosis, characterized by chronic accumulation of non-malignant lymphocytes, defective lymphocyte apoptosis, and an increased risk for the development of hematologic malignancies.[2] Function[RASN_HUMAN] Ras proteins bind GDP/GTP and possess intrinsic GTPase activity. Publication Abstract from PubMedH-Ras, K-Ras, and N-Ras are small GTPases that are important in the control of cell proliferation, differentiation, and survival, and their mutants occur frequently in human cancers. The G-domain, which catalyzes GTP hydrolysis and mediates downstream signaling, is 95% conserved between the Ras isoforms. Because of their very high sequence identity, biochemical studies done on H-Ras have been considered representative of all three Ras proteins. We show here that this is not a valid assumption. Using enzyme kinetic assays under identical conditions, we observed clear differences between the three isoforms in intrinsic catalysis of GTP by Ras in the absence and presence of the Ras-binding domain (RBD) of the c-Raf kinase protein (Raf-RBD). Given their identical active sites, isoform G-domain differences must be allosteric in origin, due to remote isoform-specific residues that affect conformational states. We present the crystal structure of N-Ras bound to a GTP analogue and interpret the kinetic data in terms of structural features specific for H-, K-, and N-Ras. The small GTPases K-Ras, N-Ras, and H-Ras have distinct biochemical properties determined by allosteric effects.,Johnson CW, Reid D, Parker JA, Salter S, Knihtila R, Kuzmic P, Mattos C J Biol Chem. 2017 Aug 4;292(31):12981-12993. doi: 10.1074/jbc.M117.778886. Epub, 2017 Jun 19. PMID:28630043[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
| ||||||||||||||||||||
