Structural highlights
Disease
VAPB_HUMAN Adult-onset proximal spinal muscular atrophy, autosomal dominant;Amyotrophic lateral sclerosis. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry.
Function
VAPB_HUMAN Participates in the endoplasmic reticulum unfolded protein response (UPR) by inducing ERN1/IRE1 activity. Involved in cellular calcium homeostasis regulation.[1] [2] [3]
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 PubMed
The Pro56Ser mutation in the human VAPB MSP domain causes a familial amyotrophic lateral sclerosis. Here we present the first structural investigation of both wild-type and Pro56Ser mutant MSP domains. The results reveal that the wild-type MSP domain is well-folded at neutral pH but can undergo acid-induced unfolding reversibly. It has a thermodynamic stability energy (DeltaG degrees (N-U)) of 7.40 kcal/mol and is also active in binding to a Nir2 peptide with a K(D) of 0.65 muM. Further determination of its crystal structure reveals that it adopts a seven-strand immunoglobulin-like beta sandwich in which Pro56 adopts the unusual cis-peptide bond conformation that appears to be critical in maintaining the characteristic S-shaped loop. Markedly, the Pro56Ser mutation renders the MSP domain insoluble in buffer. Nevertheless, as facilitated by our recent discovery that "insoluble proteins" can be solubilized in salt-free water, we have successfully characterized the residue-specific conformation of the Pro56Ser mutant by CD and heteronuclear NMR spectroscopy. The Pro56Ser mutant remains lacking of the native tight packing and secondary structures under various conditions and was further characterized as having a non-native helical conformation weakly populated at pH 3.5. Intriguingly, Pro12 located in another S-shaped loop also adopts the cis-peptide bond conformation, and its mutation to Ser is able to make the MSP domain highly insoluble and unfolded like the Pro56Ser mutant. Our study thus implies that the Pro56Ser mutation might lead to ALS by eliminating the native MSP structure, which consequently leads to aggregation and loss of functions under physiological conditions.
Elimination of the native structure and solubility of the hVAPB MSP domain by the Pro56Ser mutation that causes amyotrophic lateral sclerosis.,Shi J, Lua S, Tong JS, Song J Biochemistry. 2010 May 11;49(18):3887-97. PMID:20377183[4]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Kanekura K, Nishimoto I, Aiso S, Matsuoka M. Characterization of amyotrophic lateral sclerosis-linked P56S mutation of vesicle-associated membrane protein-associated protein B (VAPB/ALS8). J Biol Chem. 2006 Oct 6;281(40):30223-33. Epub 2006 Aug 4. PMID:16891305 doi:http://dx.doi.org/10.1074/jbc.M605049200
- ↑ Chen HJ, Anagnostou G, Chai A, Withers J, Morris A, Adhikaree J, Pennetta G, de Belleroche JS. Characterization of the properties of a novel mutation in VAPB in familial amyotrophic lateral sclerosis. J Biol Chem. 2010 Dec 17;285(51):40266-81. doi: 10.1074/jbc.M110.161398. Epub, 2010 Oct 12. PMID:20940299 doi:http://dx.doi.org/10.1074/jbc.M110.161398
- ↑ De Vos KJ, Morotz GM, Stoica R, Tudor EL, Lau KF, Ackerley S, Warley A, Shaw CE, Miller CC. VAPB interacts with the mitochondrial protein PTPIP51 to regulate calcium homeostasis. Hum Mol Genet. 2012 Mar 15;21(6):1299-311. doi: 10.1093/hmg/ddr559. Epub 2011 Nov, 30. PMID:22131369 doi:http://dx.doi.org/10.1093/hmg/ddr559
- ↑ Shi J, Lua S, Tong JS, Song J. Elimination of the native structure and solubility of the hVAPB MSP domain by the Pro56Ser mutation that causes amyotrophic lateral sclerosis. Biochemistry. 2010 May 11;49(18):3887-97. PMID:20377183 doi:10.1021/bi902057a
