1m12
From Proteopedia
(New page: 200px<br /> <applet load="1m12" size="450" color="white" frame="true" align="right" spinBox="true" caption="1m12" /> '''NMR solution structure of human Saposin C''...) |
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'''NMR solution structure of human Saposin C'''<br /> | '''NMR solution structure of human Saposin C'''<br /> | ||
==Overview== | ==Overview== | ||
| - | Saposin C binds to membranes to activate lipid degradation in lysosomes. | + | Saposin C binds to membranes to activate lipid degradation in lysosomes. To get insights into saposin C's function, we have determined its three-dimensional structure by NMR and investigated its interaction with phospholipid vesicles. Saposin C adopts the saposin-fold common to other members of the family. In contrast, the electrostatic surface revealed by the NMR structure is remarkably different. We suggest that charge distribution in the protein surface can modulate membrane interaction leading to the functional diversity of this family. We find that the binding of saposin C to phospholipid vesicles is a pH-controlled reversible process. The pH dependence of this interaction is sigmoidal, with an apparent pK(a) for binding close to 5.3. The pK(a) values of many solvent-exposed Glu residues are anomalously high and close to the binding pK(a). Our NMR data are consistent with the absence of a conformational change prior to membrane binding. All this information suggests that the negatively charged electrostatic surface of saposin C needs to be partially neutralized to trigger membrane binding. We have studied the membrane-binding behavior of a mutant of saposin C designed to decrease the negative charge of the electrostatic surface. The results support our conclusion on the importance of protein surface neutralization in binding. Since saposin C is a lysosomal protein and pH gradients occur in lysosomes, we propose that lipid degradation in the lysosome could be switched on and off by saposin C's reversible binding to membranes. |
==Disease== | ==Disease== | ||
| - | Known diseases associated with this structure: Combined SAP deficiency OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=176801 176801]], Gaucher disease, atypical OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=176801 176801]], Metachromatic leukodystrophy due to | + | Known diseases associated with this structure: Combined SAP deficiency OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=176801 176801]], Gaucher disease, atypical OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=176801 176801]], Krabbe disease, atypical OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=176801 176801]], Metachromatic leukodystrophy due to SAP-b deficiency OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=176801 176801]] |
==About this Structure== | ==About this Structure== | ||
| - | 1M12 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http:// | + | 1M12 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1M12 OCA]. |
==Reference== | ==Reference== | ||
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[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: Single protein]] | [[Category: Single protein]] | ||
| - | [[Category: Alba, E | + | [[Category: Alba, E de.]] |
[[Category: Tjandra, N.]] | [[Category: Tjandra, N.]] | ||
[[Category: Weiler, S.]] | [[Category: Weiler, S.]] | ||
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[[Category: disulfide bridges]] | [[Category: disulfide bridges]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 13:50:21 2008'' |
Revision as of 11:50, 21 February 2008
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NMR solution structure of human Saposin C
Contents |
Overview
Saposin C binds to membranes to activate lipid degradation in lysosomes. To get insights into saposin C's function, we have determined its three-dimensional structure by NMR and investigated its interaction with phospholipid vesicles. Saposin C adopts the saposin-fold common to other members of the family. In contrast, the electrostatic surface revealed by the NMR structure is remarkably different. We suggest that charge distribution in the protein surface can modulate membrane interaction leading to the functional diversity of this family. We find that the binding of saposin C to phospholipid vesicles is a pH-controlled reversible process. The pH dependence of this interaction is sigmoidal, with an apparent pK(a) for binding close to 5.3. The pK(a) values of many solvent-exposed Glu residues are anomalously high and close to the binding pK(a). Our NMR data are consistent with the absence of a conformational change prior to membrane binding. All this information suggests that the negatively charged electrostatic surface of saposin C needs to be partially neutralized to trigger membrane binding. We have studied the membrane-binding behavior of a mutant of saposin C designed to decrease the negative charge of the electrostatic surface. The results support our conclusion on the importance of protein surface neutralization in binding. Since saposin C is a lysosomal protein and pH gradients occur in lysosomes, we propose that lipid degradation in the lysosome could be switched on and off by saposin C's reversible binding to membranes.
Disease
Known diseases associated with this structure: Combined SAP deficiency OMIM:[176801], Gaucher disease, atypical OMIM:[176801], Krabbe disease, atypical OMIM:[176801], Metachromatic leukodystrophy due to SAP-b deficiency OMIM:[176801]
About this Structure
1M12 is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.
Reference
Solution structure of human saposin C: pH-dependent interaction with phospholipid vesicles., de Alba E, Weiler S, Tjandra N, Biochemistry. 2003 Dec 23;42(50):14729-40. PMID:14674747
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