A molecular model for LINC complex regulation: activation of SUN2 for KASH binding

Journal Article · Wed Aug 08 00:00:00 EDT 2018 · Molecular Biology of the Cell

DOI:https://doi.org/10.1091/mbc.e18-04-0266· OSTI ID:1625246

Jahed, Zeinab ^[1]; Vu, Uyen T. ^[2]; Fadavi, Darya ^[2]; Ke, Huimin ^[3]; Rathish, Akshay ^[2]; Kim, Samuel C. J. ^[2]; Feng, Wei ^[4]; Mofrad, Mohammad R. K. ^[5]; Weaver, Valerie Marie ^[6]

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1. Univ. of California, Berkeley, CA (United States). Molecular Cell Biomechanics Laboratory, Departments of Bioengineering and Mechanical Engineering; DOE/OSTI
2. Univ. of California, Berkeley, CA (United States). Molecular Cell Biomechanics Laboratory, Departments of Bioengineering and Mechanical Engineering
3. Chinese Academy of Sciences (CAS), Beijing (China). National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics
4. Chinese Academy of Sciences (CAS), Beijing (China). National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics
5. Univ. of California, Berkeley, CA (United States). Molecular Cell Biomechanics Laboratory, Departments of Bioengineering and Mechanical Engineering; Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Molecular Biophysics and Integrative Bioimaging Division
6. Univ. of California, San Francisco, CA (United States)

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.

• Research Organization: LBNL (Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States))
• Sponsoring Organization: USDOE
• Grant/Contract Number: AC02-05CH11231
• OSTI ID: 1625246
• Journal Information: Molecular Biology of the Cell, Journal Name: Molecular Biology of the Cell Journal Issue: 16 Vol. 29; ISSN 1059-1524
• Publisher: American Society for Cell Biology
• Country of Publication: United States
• Language: English

Related Subjects

Cell Biology