| Structural highlights
Function
GRP4_HUMAN Functions as a cation- and diacylglycerol (DAG)-regulated nucleotide exchange factor activating Ras through the exchange of bound GDP for GTP. May function in mast cells differentiation.[1] [2] [3] [4]
Publication Abstract from PubMed
RasGRPs are guanine nucleotide exchange factors that are specific for Ras or Rap, and are important regulators of cellular signaling. Aberrant expression or mutation of RasGRPs results in disease. An analysis of RasGRP1 SNP variants led to the conclusion that the charge of His 212 in RasGRP1 alters signaling activity and plasma membrane recruitment, indicating that His 212 is a pH sensor that alters the balance between the inactive and active forms of RasGRP1. To understand the structural basis for this effect we compared the structure of autoinhibited RasGRP1, determined previously, to that of active RasGRP4:H-Ras and RasGRP2:Rap1b complexes. The transition from the autoinhibited to the active form of RasGRP1 involves the rearrangement of an inter-domain linker that displaces inhibitory inter-domain interactions. His 212 is located at the fulcrum of these conformational changes, and structural features in its vicinity are consistent with its function as a pH-dependent switch.
A histidine pH sensor regulates activation of the Ras-specific guanine nucleotide exchange factor RasGRP1.,Vercoulen Y, Kondo Y, Iwig JS, Janssen A, White KA, Amini M, Barber DL, Kuriyan J, Roose JP Elife. 2017 Sep 27;6. pii: e29002. doi: 10.7554/eLife.29002. PMID:28952923[5]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Reuther GW, Lambert QT, Rebhun JF, Caligiuri MA, Quilliam LA, Der CJ. RasGRP4 is a novel Ras activator isolated from acute myeloid leukemia. J Biol Chem. 2002 Aug 23;277(34):30508-14. Epub 2002 Mar 5. PMID:11880369 doi:https://dx.doi.org/10.1074/jbc.M111330200
- ↑ Yang Y, Li L, Wong GW, Krilis SA, Madhusudhan MS, Sali A, Stevens RL. RasGRP4, a new mast cell-restricted Ras guanine nucleotide-releasing protein with calcium- and diacylglycerol-binding motifs. Identification of defective variants of this signaling protein in asthma, mastocytosis, and mast cell leukemia patients and demonstration of the importance of RasGRP4 in mast cell development and function. J Biol Chem. 2002 Jul 12;277(28):25756-74. Epub 2002 Apr 15. PMID:11956218 doi:https://dx.doi.org/10.1074/jbc.M202575200
- ↑ Li L, Yang Y, Stevens RL. RasGRP4 regulates the expression of prostaglandin D2 in human and rat mast cell lines. J Biol Chem. 2003 Feb 14;278(7):4725-9. Epub 2002 Dec 18. PMID:12493770 doi:https://dx.doi.org/10.1074/jbc.C200635200
- ↑ Katsoulotos GP, Qi M, Qi JC, Tanaka K, Hughes WE, Molloy TJ, Adachi R, Stevens RL, Krilis SA. The Diacylglycerol-dependent translocation of ras guanine nucleotide-releasing protein 4 inside a human mast cell line results in substantial phenotypic changes, including expression of interleukin 13 receptor alpha2. J Biol Chem. 2008 Jan 18;283(3):1610-21. Epub 2007 Nov 16. PMID:18024961 doi:https://dx.doi.org/M707042200
- ↑ Vercoulen Y, Kondo Y, Iwig JS, Janssen A, White KA, Amini M, Barber DL, Kuriyan J, Roose JP. A histidine pH sensor regulates activation of the Ras-specific guanine nucleotide exchange factor RasGRP1. Elife. 2017 Sep 27;6. pii: e29002. doi: 10.7554/eLife.29002. PMID:28952923 doi:https://dx.doi.org/10.7554/eLife.29002
|
