Mammalian SUN protein interaction networks at the inner nuclear membrane and their role in laminopathy disease processes

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dc.cclicenceCC-BY-NCen
dc.contributor.authorHaque, F.
dc.contributor.authorMazzeo, D.
dc.contributor.authorPatel, J.
dc.contributor.authorSmallwood, Dawn T.
dc.contributor.authorEllis, J.A.
dc.contributor.authorShanahan, C.M.
dc.contributor.authorShackleton, S.
dc.date.acceptance2009-11-21
dc.date.accessioned2019-11-13T08:49:42Z
dc.date.available2019-11-13T08:49:42Z
dc.date.issued2009-11-21
dc.descriptionThe Publisher's final version can be found by following the DOI link.en
dc.description.abstractThe nuclear envelope (NE) LINC complex, in mammals comprised of SUN domain and nesprin proteins, provides a direct connection between the nuclear lamina and the cytoskeleton, which contributes to nuclear positioning and cellular rigidity. SUN1 and SUN2 interact with lamin A, but lamin A is only required for NE localization of SUN2, and it remains unclear how SUN1 is anchored. Here, we identify emerin and short nesprin-2 isoforms as novel nucleoplasmic binding partners of SUN1/2. These have overlapping binding sites distinct from the lamin A binding site. However, we demonstrate that tight association of SUN1 with the nuclear lamina depends upon a short motif within residues 209-228, a region that does not interact significantly with known SUN1 binding partners. Moreover, SUN1 localizes correctly in cells lacking emerin. Importantly then, the major determinant of SUN1 NE localization has yet to be identified. We further find that a subset of lamin A mutations, associated with laminopathies Emery-Dreifuss muscular dystrophy (EDMD) and Hutchinson-Gilford progeria syndrome (HGPS), disrupt lamin A interaction with SUN1 and SUN2. Despite this, NE localization of SUN1 and SUN2 is not impaired in cell lines from either class of patients. Intriguingly, SUN1 expression at the NE is instead enhanced in a significant proportion of HGPS but not EDMD cells and strongly correlates with pre-lamin A accumulation due to preferential interaction of SUN1 with pre-lamin A. We propose that these different perturbations in lamin A-SUN protein interactions may underlie the opposing effects of EDMD and HGPS mutations on nuclear and cellular mechanics.en
dc.exception.ref2021codes254aen
dc.funderWellcome Trusten
dc.funder.otherBritish Heart Foundationen
dc.funder.otherBiotechnology and Biological Sciences Research Council, Swindon, United Kingdom studentship awarded (to J. T. P.).en
dc.identifier.citationHaque, F., Mazzeo, D., Patel, J.T., Smallwood, D.T., Ellis, J.A., Shanahan, C.M., Shackleton, S. (2010) Mammalian SUN protein interaction networks at the inner nuclear membrane and their role in laminopathy disease processes. The Journal of Biological Chemistry, 285(5), pp.3487–3498.en
dc.identifier.doihttps://doi.org/10.1074/jbc.M109.071910
dc.identifier.urihttps://dora.dmu.ac.uk/handle/2086/18781
dc.language.isoenen
dc.peerreviewedYesen
dc.publisherAmerican Society for Biochemistry and Molecular Biologyen
dc.researchinstituteInstitute for Allied Health Sciences Researchen
dc.subjectCell Nucleusen
dc.subjectIntracellular Signaling Peptides and Proteinsen
dc.subjectLamin Type Aen
dc.subjectMembrane Proteinsen
dc.subjectNuclear Envelopeen
dc.subjectMuscular Dystrophyen
dc.subjectProgeriaen
dc.titleMammalian SUN protein interaction networks at the inner nuclear membrane and their role in laminopathy disease processesen
dc.typeArticleen

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