TY - JOUR
T1 - The small GTPases Ras and Rheb studied by multidimensional NMR spectroscopy
T2 - Structure and function
AU - Schöpel, Miriam
AU - Potheraveedu, Veena Nambiar
AU - Al-Harthy, Thuraya
AU - Abdel-Jalil, Raid
AU - Heumann, Rolf
AU - Stoll, Raphael
N1 - Funding Information:
We are extremely grateful to Gregor Barchan, Martin Gartmann, and Hans-Jochen Hauswald for expert technical help. We are also indebted to all former co-workers on this project, in particular Drs. Berghaus, Jockers, and Schwarten. This work was supported by a DFG grant (SFB 642, project A6). In addition, R. S. gratefully recognises generous support from the BMBF, FCI, Proteincenter (NRW Center of Excellence), RUB Protein Research Department, and Krebshilfe e.V. (109776, 109777). M.S. thanks the Ruhr University Research SchoolPlus funded by Germany's Excellence Initiative for financial support.
Publisher Copyright:
© 2017, Miriam Schöpel et al., published by De Gruyter.
PY - 2017/5/1
Y1 - 2017/5/1
N2 - Ras GTPases are key players in cellular signalling because they act as binary switches. These states manifest through toggling between an active (GTP-loaded) and an inactive (GDP-loaded) form. The hydrolysis and replenishing of GTP is controlled by two additional protein classes: GAP (GTPase-activating)- and GEF (Guanine nucleotide exchange factors)-proteins. The complex interplay of the proteins is known as the GTPase-cycle. Several point mutations of the Ras protein deregulate this cycle. Mutations in Ras are associated with up to one-third of human cancers. The three isoforms of Ras (H, N, K) exhibit high sequence similarity and mainly differ in a region called HVR (hypervariable region). The HVR governs the differential action and cellular distribution of the three isoforms. Rheb is a Ras-like GTPase that is conserved from yeast to mammals. Rheb is mainly involved in activation of cell growth through stimulation of mTORC1 activity. In this review, we summarise multidimensional NMR studies on Rheb and Ras carried out to characterise their structure-function relationship and explain how the activity of these small GTPases can be modulated by low molecular weight compounds. These might help to design GTPase-selective antagonists for treatment of cancer and brain disease.
AB - Ras GTPases are key players in cellular signalling because they act as binary switches. These states manifest through toggling between an active (GTP-loaded) and an inactive (GDP-loaded) form. The hydrolysis and replenishing of GTP is controlled by two additional protein classes: GAP (GTPase-activating)- and GEF (Guanine nucleotide exchange factors)-proteins. The complex interplay of the proteins is known as the GTPase-cycle. Several point mutations of the Ras protein deregulate this cycle. Mutations in Ras are associated with up to one-third of human cancers. The three isoforms of Ras (H, N, K) exhibit high sequence similarity and mainly differ in a region called HVR (hypervariable region). The HVR governs the differential action and cellular distribution of the three isoforms. Rheb is a Ras-like GTPase that is conserved from yeast to mammals. Rheb is mainly involved in activation of cell growth through stimulation of mTORC1 activity. In this review, we summarise multidimensional NMR studies on Rheb and Ras carried out to characterise their structure-function relationship and explain how the activity of these small GTPases can be modulated by low molecular weight compounds. These might help to design GTPase-selective antagonists for treatment of cancer and brain disease.
KW - Ras
KW - Rheb
KW - ligand binding
KW - nuclear magnetic resonance (NMR)
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U2 - 10.1515/hsz-2016-0276
DO - 10.1515/hsz-2016-0276
M3 - Review article
C2 - 28475102
AN - SCOPUS:85017590638
SN - 1431-6730
VL - 398
SP - 577
EP - 588
JO - Biological Chemistry
JF - Biological Chemistry
IS - 5-6
ER -