Document Detail


Structural requirements for the assembly of LINC complexes and their function in cellular mechanical stiffness.
MedLine Citation:
PMID:  18396275     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The evolutionary-conserved interactions between KASH and SUN domain-containing proteins within the perinuclear space establish physical connections, called LINC complexes, between the nucleus and the cytoskeleton. Here, we show that the KASH domains of Nesprins 1, 2 and 3 interact promiscuously with luminal domains of Sun1 and Sun2. These constructs disrupt endogenous LINC complexes as indicated by the displacement of endogenous Nesprins from the nuclear envelope. We also provide evidence that KASH domains most probably fit a pocket provided by SUN domains and that post-translational modifications are dispensable for that interaction. We demonstrate that the disruption of endogenous LINC complexes affect cellular mechanical stiffness to an extent that compares to the loss of mechanical stiffness previously reported in embryonic fibroblasts derived from mouse lacking A-type lamins, a mouse model of muscular dystrophies and cardiomyopathies. These findings support a model whereby physical connections between the nucleus and the cytoskeleton are mediated by interactions between diverse combinations of Sun proteins and Nesprins through their respective evolutionary-conserved domains. Furthermore, they emphasize, for the first time, the relevance of LINC complexes in cellular mechanical stiffness suggesting a possible involvement of their disruption in various laminopathies, a group of human diseases linked to mutations of A-type lamins.
Authors:
P J Stewart-Hutchinson; Christopher M Hale; Denis Wirtz; Didier Hodzic
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2008-03-12
Journal Detail:
Title:  Experimental cell research     Volume:  314     ISSN:  0014-4827     ISO Abbreviation:  Exp. Cell Res.     Publication Date:  2008 May 
Date Detail:
Created Date:  2008-04-30     Completed Date:  2008-06-19     Revised Date:  2014-09-21    
Medline Journal Info:
Nlm Unique ID:  0373226     Medline TA:  Exp Cell Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1892-905     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Amino Acid Sequence
Animals
Binding Sites
Biomechanical Phenomena
Cell Line
Cytoskeleton / physiology
Humans
Intracellular Signaling Peptides and Proteins / chemistry*,  metabolism
Membrane Proteins / chemistry*,  metabolism
Mice
Microfilament Proteins / chemistry*,  metabolism
Microtubule-Associated Proteins / chemistry*,  metabolism
Molecular Sequence Data
Nerve Tissue Proteins / chemistry*,  metabolism
Nuclear Lamina / chemistry,  physiology
Nuclear Proteins / chemistry*,  metabolism
Protein Structure, Tertiary
Grant Support
ID/Acronym/Agency:
R01 GM084204/GM/NIGMS NIH HHS; R21 EB006890/EB/NIBIB NIH HHS; R21 EB006890-01/EB/NIBIB NIH HHS; R21 EB006890-02/EB/NIBIB NIH HHS; R21#EB006890/EB/NIBIB NIH HHS
Chemical
Reg. No./Substance:
0/Intracellular Signaling Peptides and Proteins; 0/Membrane Proteins; 0/Microfilament Proteins; 0/Microtubule-Associated Proteins; 0/Nerve Tissue Proteins; 0/Nuclear Proteins; 0/SUN1 protein, human; 0/SUN2 protein, human; 0/SYNE1 protein, human; 0/SYNE2 protein, human; 0/nesprin 3 protein, human
Comments/Corrections

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