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A molecular model for LINC complex regulation: activation of SUN2 for KASH binding
- Source :
- Molecular Biology of the Cell, Molecular biology of the cell, vol 29, iss 16, Jahed, Z; Vu, UT; Fadavi, D; Ke, H; Rathish, A; Kim, SCJ; et al.(2018). A molecular model for LINC complex regulation: Activation of SUN2 for KASH binding. Molecular Biology of the Cell, 29(16), 2012-2023. doi: 10.1091/mbc.E18-04-0266. UC Berkeley: Retrieved from: http://www.escholarship.org/uc/item/6xq0p2rr
- Publication Year :
- 2018
- Publisher :
- American Society for Cell Biology (ASCB), 2018.
-
Abstract
- Linkers of the nucleoskeleton and cytoskeleton are key molecular complexes that span the nuclear envelope (NE) and provide a direct linkage between the nucleoskeleton and cytoskeleton. Two major components of these complexes are members of the SUN and KASH protein families that interact in the perinuclear space to allow the transmission of mechanochemical signals across the NE. Structural details of the mammalian SUN domain protein SUN2 have established that SUN2 must form a trimer to bind to KASH, and that this trimerization is mediated through two predicted coiled-coil regions of the protein, CC1 and CC2, which precede the SUN domain. Recent crystallographic data suggest that CC2-SUN formed an unexpected autoinhibited monomer unable to bind to KASH. These structural insights raise the question of how full-length SUN2 transitions from a monomer to a trimer inside the NE. In this study we used a computational approach to model a fragment of SUN2 containing CC1, CC2, and the SUN domain. We observed the dynamics of these modeled structures using ∼1 μs molecular dynamics simulations and showed that the interplay between CC1 and CC2 may be sufficient for the release of CC2-SUN2 from its autoinhibited state. Additionally, using our models and gel filtration analysis, we show the involvement of an E452 residue on CC1 in the monomer–­trimer transition of SUN2. Intriguingly, mutations in this residue have been seen in muscular dystrophy–associated SUN2 variants. Finally, we propose a Ca2+-dependent monomer–trimer transition of SUN2.
- Subjects :
- Models, Molecular
0301 basic medicine
Protein Structure
Secondary
Protein family
Molecular model
Nuclear Envelope
1.1 Normal biological development and functioning
LINC complex
Telomere-Binding Proteins
Trimer
Plasma protein binding
Molecular Dynamics Simulation
Biology
Medical and Health Sciences
Models, Biological
Protein Structure, Secondary
Mice
03 medical and health sciences
0302 clinical medicine
Protein structure
Underpinning research
Models
Animals
Amino Acid Sequence
Nuclear protein
Molecular Biology
Ions
Nuclear Functions
Intracellular Signaling Peptides and Proteins
Molecular
Membrane Proteins
Nuclear Proteins
Articles
Cell Biology
Biological Sciences
Biological
030104 developmental biology
Multiprotein Complexes
Mutation
Biophysics
Calcium
Generic health relevance
Protein Multimerization
SUN domain
030217 neurology & neurosurgery
Developmental Biology
Protein Binding
Subjects
Details
- ISSN :
- 19394586 and 10591524
- Volume :
- 29
- Database :
- OpenAIRE
- Journal :
- Molecular Biology of the Cell
- Accession number :
- edsair.doi.dedup.....8fa1b7eb83a27895993c3627bda0a002
- Full Text :
- https://doi.org/10.1091/mbc.e18-04-0266