Characterization of human saposins by NMR spectroscopy

Biochemistry
Michael JohnHorst Kessler

Abstract

Saposins are lipid-binding and membrane-perturbing glycoproteins of the mammalian lysosomes involved in sphingolipid and membrane digestion. Although the four human saposins (Saps), A-D, are sequence-related, they are responsible for the activation of different steps in the cascade of lysosomal glycosphingolipid degradation. Saposin activity is maximal under acidic conditions, and the pH dependence of lipid and membrane binding has been assigned to conformational variability. We have employed solution NMR spectroscopy to all four (15)N-labeled human saposins at both neutral and acidic pH. Using backbone NOEs and residual dipolar couplings, the "saposin fold" comprising five alpha-helices was confirmed for Sap-A, Sap-C, and Sap-D. Structural variations within these proteins are in the order of variations between the known structures of Sap-C and NK-lysin. In contrast, Sap-B yielded spectra of very poor quality, presumably due to conformational heterogeneity and molecular association. Sap-D exists in a slow dynamic equilibrium of two conformational states with yet unknown function. At pH 4.0, where all saposins are highly unstable, Sap-C undergoes a transition to a specific dimeric state, which is likely to resemble the structure...Continue Reading

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Citations

Jun 13, 2009·Journal of Computer-aided Molecular Design·Melissa R LandonDagmar Ringe
Aug 21, 2009·The Journal of Biological Chemistry·Leah A Martin-VisscherJohn C Vederas
Dec 18, 2009·Human Molecular Genetics·Ying SunGregory A Grabowski
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Feb 15, 2018·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·María Garrido-ArandiaLuis F Pacios
Apr 10, 2021·Biophysical Chemistry·Sonia Sanz MuñozCéline Galvagnion
Jan 22, 2011·Journal of Medicinal Chemistry·Juan J MaruganChristopher P Austin
Jul 28, 2012·Journal of Medicinal Chemistry·Jingbo XiaoJuan J Marugan

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