Matches in SemOpenAlex for { <https://semopenalex.org/work/W2761972984> ?p ?o ?g. }
- W2761972984 abstract "ABSTRACT The human zinc metalloprotease ZMPSTE24 is an integral membrane protein critical for the final step in the biogenesis of the nuclear scaffold protein lamin A, encoded by LMNA . After farnesylation and carboxyl methylation of its C-terminal CAAX motif, the lamin A precursor, prelamin A, undergoes proteolytic removal of its modified C-terminal 15 amino acids by ZMPSTE24. Mutations in LMNA or ZMPSTE24 that impede this prelamin A cleavage step cause the premature aging disease Hutchinson-Gilford Progeria Syndrome (HGPS) and the related progeroid disorders mandibuloacral dysplasia-type B (MAD-B) and restrictive dermopathy (RD). Here we report a “humanized yeast” system to assay ZMPSTE24-dependent cleavage of prelamin A and examine the eight known disease-associated ZMPSTE24 missense mutations. All show diminished prelamin A processing and fall into three classes, with defects in activity, protein stability, or both. Notably, some ZMPSTE24 mutants can be rescued by deleting the E3 ubiquitin ligase Doa10, involved in ER-associated degradation of misfolded membrane proteins, or by treatment with the proteasome inhibitor bortezomib, which may have important therapeutic implications for some patients. We also show that ZMPSTE24-mediated prelamin A cleavage can be uncoupled from the recently discovered role of ZMPSTE24 in clearance of ER membrane translocon-clogged substrates. Together with the crystal structure of ZMPSTE24, this “humanized yeast system” can guide structure-function studies to uncover mechanisms of prelamin A cleavage, translocon unclogging, and membrane protein folding and stability." @default.
- W2761972984 created "2017-10-20" @default.
- W2761972984 creator A5017414403 @default.
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- W2761972984 creator A5081544632 @default.
- W2761972984 creator A5088882821 @default.
- W2761972984 date "2017-10-04" @default.
- W2761972984 modified "2023-09-27" @default.
- W2761972984 title "<i>ZMPSTE24</i>Missense Mutations that Cause Progeroid Diseases Decrease Prelamin A Cleavage Activity and/or Protein Stability" @default.
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- W2761972984 doi "https://doi.org/10.1101/198069" @default.
- W2761972984 hasPublicationYear "2017" @default.
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