2dob | pdb_00002dob
Crystal Structure of Human Saposin A
Structural highlights
Disease[SAP_HUMAN] Defects in PSAP are the cause of combined saposin deficiency (CSAPD) [MIM:611721]; also known as prosaposin deficiency. CSAPD is due to absence of all saposins, leading to a fatal storage disorder with hepatosplenomegaly and severe neurological involvement.[1] [2] Defects in PSAP saposin-B region are the cause of leukodystrophy metachromatic due to saposin-B deficiency (MLD-SAPB) [MIM:249900]. MLD-SAPB is an atypical form of metachromatic leukodystrophy. It is characterized by tissue accumulation of cerebroside-3-sulfate, demyelination, periventricular white matter abnormalities, peripheral neuropathy. Additional neurological features include dysarthria, ataxic gait, psychomotr regression, seizures, cognitive decline and spastic quadriparesis. Defects in PSAP saposin-C region are the cause of atypical Gaucher disease (AGD) [MIM:610539]. Affected individuals have marked glucosylceramide accumulation in the spleen without having a deficiency of glucosylceramide-beta glucosidase characteristic of classic Gaucher disease, a lysosomal storage disorder.[3] [4] Defects in PSAP saposin-A region are the cause of atypical Krabbe disease (AKRD) [MIM:611722]. AKRD is a disorder of galactosylceramide metabolism. AKRD features include progressive encephalopathy and abnormal myelination in the cerebral white matter resembling Krabbe disease.[5] Note=Defects in PSAP saposin-D region are found in a variant of Tay-Sachs disease (GM2-gangliosidosis). Function[SAP_HUMAN] The lysosomal degradation of sphingolipids takes place by the sequential action of specific hydrolases. Some of these enzymes require specific low-molecular mass, non-enzymic proteins: the sphingolipids activator proteins (coproteins). Saposin-A and saposin-C stimulate the hydrolysis of glucosylceramide by beta-glucosylceramidase (EC 3.2.1.45) and galactosylceramide by beta-galactosylceramidase (EC 3.2.1.46). Saposin-C apparently acts by combining with the enzyme and acidic lipid to form an activated complex, rather than by solubilizing the substrate. Saposin-B stimulates the hydrolysis of galacto-cerebroside sulfate by arylsulfatase A (EC 3.1.6.8), GM1 gangliosides by beta-galactosidase (EC 3.2.1.23) and globotriaosylceramide by alpha-galactosidase A (EC 3.2.1.22). Saposin-B forms a solubilizing complex with the substrates of the sphingolipid hydrolases. Saposin-D is a specific sphingomyelin phosphodiesterase activator (EC 3.1.4.12). 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 PubMedSaposins A and C are sphingolipid activator proteins required for the lysosomal breakdown of galactosylceramide and glucosylceramide, respectively. The saposins interact with lipids, leading to an enhanced accessibility of the lipid headgroups to their cognate hydrolases. We have determined the crystal structures of human saposins A and C to 2.0 Angstroms and 2.4 Angstroms, respectively, and both reveal the compact, monomeric saposin fold. We confirmed that these two proteins were monomeric in solution at pH 7.0 by analytical centrifugation. However, at pH 4.8, in the presence of the detergent C(8)E(5), saposin A assembled into dimers, while saposin C formed trimers. Saposin B was dimeric under all conditions tested. The self-association of the saposins is likely to be relevant to how these small proteins interact with lipids, membranes, and hydrolase enzymes. Crystal structures of saposins A and C.,Ahn VE, Leyko P, Alattia JR, Chen L, Prive GG Protein Sci. 2006 Aug;15(8):1849-57. Epub 2006 Jul 5. PMID:16823039[6] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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