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We provided a first, thorough biochemical and cell biological characterization of LUMA, the 45-kDa protein identified with our proteomics screen.
Orthologs of LUMA are present in many species. Sequence alignments show a highly conserved protein. Not as highly conserved, but with fair similarity, LUMA orthologs are found even in bacteria and plants, but not in S. cerevisiae or in the nematode C. elegans. LUMA does not share any homology with other, better-characterized proteins.
Abbildung: LUMA Orthologs - A similar membrane topology based on sequence alignments is evident for LUMA sequences obtained from different species.
Therefore, the primary structure does not provide hints towards LUMA functions. It suggests, however, a membrane topology consisting of 4 transmembrane domains (TMDs) and a large hydrophilic domain between predicted TMD 1 and TMD 2 comprising approximately two-thirds of the LUMA sequence. LUMA is targeted in a A-type-lamin-dependent manner to the inner nuclear membrane, where it gets immobilized. In addition to this pool of LUMA, an unusually large LUMA pool is still present in other domains of the endoplasmic reticulum (ER). By overexpressing truncation mutants, by limited proteolysis on membrane-inserted LUMA and by testing the accessibility of antibody epitopes in digitonin-permeabilized cells, we could show that LUMA indeed passes the membrane four times and that both its termini are localized on the cytoplasmic/nucleoplasmic side of the ER membrane. The large hydrophilic domain is localized to the ER lumen.
Abbildung: LUMATopology and Interactions - LUMA oligomerizes and interacts with emerin. Both interactions depend on LUMA transmembrane domains.
Targeting and oligomerization of LUMA depends on its transmembrane domains, also its interaction with the inner-nuclear-membrane protein emerin. Overexpression of LUMA and its truncation mutants displaces emerin at least partially from the INM and causes an aberrant emerin distribution. Since this is a hallmark of Emery-Dreifuss muscular dystrophy, LUMA may be involved in pathological mechanisms leading to dystrophic diseases. From its structural features and its properties regarding interactions with other proteins and its distribution in the ER we propose that LUMA is be a tetraspanin-like organizer of protein complexes of the ER and particularly of the INM (Bengtsson and Otto, 2008).
Abbildung: LUMA Targeting Depends on A-Type Lamins - Endogenous LUMA is partially retained at the NE only in mouse embryonic fibroblasts (MEFs) from wild-type mice. MEFs from LMNA-knockout mice lacking A-type lamins do not support LUAM accumulation at the NE
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Henning Otto / updated: 12.04.2011