Oncology and Molecular Medicine

Oncology and Molecular Medicine


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Motta M.,Oncology and Molecular Medicine | Tatti M.,Oncology and Molecular Medicine | Torreri P.,Instituto Superiore Of Sanita | Tartaglia M.,Oncology and Molecular Medicine | Salvioli R.,Oncology and Molecular Medicine
Human molecular genetics | Year: 2014

Saposin (Sap) C is an essential cofactor for the lysosomal degradation of glucosylceramide (GC) by glucosylceramidase (GCase) and its functional impairment underlies a rare variant form of Gaucher disease (GD). Sap C promotes rearrangement of lipid organization in lysosomal membranes favoring substrate accessibility to GCase. It is characterized by six invariantly conserved cysteine residues involved in three intramolecular disulfide bonds, which make the protein remarkably stable to acid environment and degradation. Five different mutations (i.e. p.C315S, p.342_348FDKMCSKdel, p.L349P, p.C382G and p.C382F) have been identified to underlie Sap C deficiency. The molecular mechanism by which these mutations affect Sap C function, however, has not been delineated in detail. Here, we characterized biochemically and functionally four of these gene lesions. We show that all Sap C mutants are efficiently produced, and exhibit lipid-binding properties, modulatory behavior on GCase activity and subcellular localization comparable with those of the wild-type protein. We then delineated the structural rearrangement of these mutants, documenting that most proteins assume diverse aberrant disulfide bridge arrangements, which result in a substantial diminished half-life, and rapid degradation via autophagy. These findings further document the paramount importance of disulfide bridges in the stability of Sap C and provide evidence that accelerated degradation of the Sap C mutants is the underlying pathogenetic mechanism of Sap C deficiency. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.


PubMed | Oncology and Molecular Medicine., Oncology and Molecular Medicine and Instituto Superiore Of Sanita
Type: Journal Article | Journal: Human molecular genetics | Year: 2014

Saposin (Sap) C is an essential cofactor for the lysosomal degradation of glucosylceramide (GC) by glucosylceramidase (GCase) and its functional impairment underlies a rare variant form of Gaucher disease (GD). Sap C promotes rearrangement of lipid organization in lysosomal membranes favoring substrate accessibility to GCase. It is characterized by six invariantly conserved cysteine residues involved in three intramolecular disulfide bonds, which make the protein remarkably stable to acid environment and degradation. Five different mutations (i.e. p.C315S, p.342_348FDKMCSKdel, p.L349P, p.C382G and p.C382F) have been identified to underlie Sap C deficiency. The molecular mechanism by which these mutations affect Sap C function, however, has not been delineated in detail. Here, we characterized biochemically and functionally four of these gene lesions. We show that all Sap C mutants are efficiently produced, and exhibit lipid-binding properties, modulatory behavior on GCase activity and subcellular localization comparable with those of the wild-type protein. We then delineated the structural rearrangement of these mutants, documenting that most proteins assume diverse aberrant disulfide bridge arrangements, which result in a substantial diminished half-life, and rapid degradation via autophagy. These findings further document the paramount importance of disulfide bridges in the stability of Sap C and provide evidence that accelerated degradation of the Sap C mutants is the underlying pathogenetic mechanism of Sap C deficiency.


PubMed | Mount Sinai School of Medicine, Oncology and Molecular Medicine., Genetics and Rare Diseases Research Division, CINECA and Instituto Superiore Of Sanita
Type: Journal Article | Journal: Human molecular genetics | Year: 2016

SHOC2 is a scaffold protein composed almost entirely by leucine-rich repeats (LRRs) and having an N-terminal region enriched in alternating lysine and glutamate/aspartate residues (KEKE motifs). SHOC2 acts as a positive modulator of the RAS-RAF-MEK-ERK signalling cascade by favouring stable RAF1 interaction with RAS. We previously reported that the p.Ser2Gly substitution in SHOC2 underlies Mazzanti syndrome, a RASopathy clinically overlapping Noonan syndrome, promoting N-myristoylation and constitutive targeting of the mutant to the plasma membrane. We also documented transient nuclear translocation of wild-type SHOC2 upon EGF stimulation, suggesting a more complex function in signal transduction.Here, we characterized the domains controlling SHOC2 shuttling between the nucleus and cytoplasm, and those contributing to SHOC2


Motta M.,Oncology and Molecular Medicine | Camerini S.,Viale Regina Elena | Tatti M.,Oncology and Molecular Medicine | Casella M.,Viale Regina Elena | And 4 more authors.
Human Molecular Genetics | Year: 2014

Saposin (Sap)Cis anessential cofactor for the lysosomal degradation of glucosylceramide (GC) byglucosylceramidase (GCase) and its functional impairment underlies a rare variant form of Gaucher disease (GD). SapCpromotes rearrangement of lipid organization in lysosomalmembranes favoring substrate accessibility toGCase. It is characterized by six invariantly conserved cysteine residues involved in three intramolecular disulfide bonds, which make the protein remarkably stable to acid environment and degradation. Five different mutations (i.e. p.C315S, p.342_348FDKMCSKdel, p.L349P, p.C382G and p.C382F) have been identified to underlie Sap C deficiency. The molecular mechanism by which thesemutations affect Sap C function, however, has not been delineated in detail. Here, we characterized biochemically and functionally four of these gene lesions.Weshow that all Sap Cmutants are efficiently produced, and exhibit lipid-binding properties, modulatory behavior on GCase activityandsubcellular localization comparable with those of the wild-type protein.Wethen delineated the structural rearrangement of thesemutants,documenting thatmostproteinsassumediverse aberrant disulfide bridge arrangements, which result in a substantial diminished half-life, and rapid degradation via autophagy. These findings further document the paramount importance of disulfide bridges in the stability of Sap C and provide evidence that accelerated degradation of the Sap C mutants is the underlying pathogenetic mechanism of Sap C deficiency. © The Author 2014.

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