2rr3 | pdb_00002rr3
Solution structure of the complex between human VAP-A MSP domain and human OSBP FFAT motif
Structural highlights
Function[VAPA_HUMAN] May play a role in vesicle trafficking.[1] [2] [OSBP1_HUMAN] Binds cholesterol and a range of oxysterols. Cholesterol binding promotes the formation of a complex with PP2A and a tyrosine phosphatase which dephosphorylate ERK1/2, whereas 25-hydroxycholesterol causes its disassembly. Regulates cholesterol efflux by decreasing ABCA1 stability.[3] [4] Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMedOxysterol-binding protein (OSBP), a cytosolic receptor of cholesterol and oxysterols, is recruited to the endoplasmic reticulum by binding to the cytoplasmic major sperm protein (MSP) domain of integral endoplasmic reticulum protein VAMP-associated protein-A (VAP-A), a process essential for the stimulation of sphingomyelin synthesis by 25-hydroxycholesterol. To delineate the interaction mechanism between VAP-A and OSBP, we determined the complex structure between the VAP-A MSP domain (VAP-A(MSP)) and the OSBP fragment containing a VAP-A binding motif FFAT (OSBP(F)) by NMR. This solution structure explained that five of six conserved residues in the FFAT motif are required for the stable complex formation, and three of five, including three critical intermolecular electrostatic interactions, were not explained before. By combining NMR relaxation and titration, isothermal titration calorimetry, and mutagenesis experiments with structural information, we further elucidated the detailed roles of the FFAT motif and underlying motions of VAP-A(MSP), OSBP(F), and the complex. Our results show that OSBP(F) is disordered in the free state, and VAP-A(MSP) and OSBP(F) form a final complex by means of intermediates, where electrostatic interactions through acidic residues, including an acid patch preceding the FFAT motif, probably play a collective role. Additionally, we report that the mutation that causes the familial motor neuron disease decreases the stability of the MSP domain. Electrostatic interaction between oxysterol-binding protein and VAMP-associated protein A revealed by NMR and mutagenesis studies.,Furuita K, Jee J, Fukada H, Mishima M, Kojima C J Biol Chem. 2010 Apr 23;285(17):12961-70. Epub 2010 Feb 23. PMID:20178991[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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