Abstract
Marinesco-Sjögren syndrome (MSS) is an autosomal recessive, neurodegenerative, multisystem disorder characterized by severe phenotypes developing in infancy. Recently, mutations in the endoplasmic reticulum (ER)-associated co-chaperone SIL1/BAP were identified to be the major cause of MSS. SIL1 acts as a nucleotide exchange factor for BiP, the ER Hsp70 orthologue, which plays an essential role in the folding and assembly of nascent polypeptide chains in the ER. SIL1 facilitates the release of BiP from unfolded protein substrates, enabling the subsequent folding and transport of the protein. Although most mutations leading to MSS result in deletion of the majority of the protein, three separate mutations have been identified that disrupt only the last five or six amino acids of the protein, which were assumed to encode a divergent ER retention motif. This study presents an in depth analysis of two of these mutants and reveals that the phenotype in the affected individuals is not likely to be due to depletion of SIL1 from the ER via secretion. Instead, our analyses show that the mutant proteins are particularly unstable and either form large aggregates in the ER or are rapidly degraded via the proteasome. In agreement with our findings, homology modeling suggests that the very C-terminal residues of SIL1 play a role in its structural integrity rather than its localization. These new insights might be a first step toward a possible pharmacological treatment of certain types of MSS by specifically stabilizing the mutant SIL1 protein.
Highlights
Mutations in SIL1 can cause Marinesco-Sjogren syndrome
Generation of cDNA Encoding the MSS-associated ⌬1366 Mutant—The vast majority of SIL1 mutations that cause Marinesco-Sjögren syndrome result in the deletion of large portions of the protein that would be expected to affect the predicted BiP-interacting regions encoded by exons 6 and 9
In 1987, Munro and Pelham [30] noted that a number of soluble, resident endoplasmic reticulum (ER) proteins possess the tetrapeptide, KDEL, at their C terminus and postulated that this sequence might be responsible for preventing their secretion
Summary
Mutations in SIL1 can cause Marinesco-Sjogren syndrome. Results: Deletion or mutation of the last 5– 6 amino acids destabilized SIL1. In agreement with our findings, homology modeling suggests that the very C-terminal residues of SIL1 play a role in its structural integrity rather than its localization These new insights might be a first step toward a possible pharmacological treatment of certain types of MSS by stabilizing the mutant SIL1 protein. BiP knock-out mice die at embryonic day 3.5 [22], and the AB5 subtilase cytotoxin exerts its lethal effects by cleaving BiP between the nucleotide binding domain and the substrate binding domain [23], presumably deregulating the binding and release of BiP to client proteins It came as no small surprise when linkage disequilibrium studies mapped MSS disease-causing mutations to the SIL1 gene [24, 25]. In keeping with this, modeling of the SIL1 structure suggests that its C-terminal region is structured and forms a number of stabilizing contacts with the rest of the molecule
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