Role of KASH domain lengths in the regulation of LINC complexes

Jahed, Zeinab; Hao, Hongyan; Thakkar, Vyom; Vu, Uyen T.; Valdez, Venecia A.; Rathish, Akshay; Tolentino, Chris; Kim, Samuel C.  J.; Fadavi, Darya; Starr, Daniel A.; Mofrad, Mohammad R.  K.

doi:10.1091/mbc.e19-02-0079

Role of KASH domain lengths in the regulation of LINC complexes

Journal Article · Mon Jul 22 00:00:00 EDT 2019 · Molecular Biology of the Cell

DOI:https://doi.org/10.1091/mbc.e19-02-0079· OSTI ID:1633237

Jahed, Zeinab ^[1]; Hao, Hongyan ^[2]; Thakkar, Vyom ^[1]; Vu, Uyen T. ^[1]; Valdez, Venecia A. ^[2]; Rathish, Akshay ^[1]; Tolentino, Chris ^[1]; Kim, Samuel C. J. ^[1]; Fadavi, Darya ^[1]; Starr, Daniel A. ^[2]; Mofrad, Mohammad R. K. ^[3]

Univ. of California, Berkeley, CA (United States). Depts. of Bioengineering and Mechanical Engineering,
Univ. of California, Davis, CA (United States). Dept. of Molecular and Cellular Biology
Univ. of California, Berkeley, CA (United States). Depts. of Bioengineering and Mechanical Engineering; Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Molecular Biophysics and Integrative Bioimaging Division

The linker of the nucleoskeleton and cytoskeleton (LINC) complex is formed by the conserved interactions between Sad-1 and UNC-84 (SUN) and Klarsicht, ANC-1, SYNE homology (KASH) domain proteins, providing a physical coupling between the nucleoskeleton and cytoskeleton that mediates the transfer of physical forces across the nuclear envelope. The LINC complex can perform distinct cellular functions by pairing various KASH domain proteins with the same SUN domain protein. For example, in Caenorhabditis elegans, SUN protein UNC-84 binds to two KASH proteins UNC-83 and ANC-1 to mediate nuclear migration and anchorage, respectively. In addition to distinct cytoplasmic domains, the luminal KASH domain also varies among KASH domain proteins of distinct functions. Here, we combined in vivo C. elegans genetics and in silico molecular dynamics simulations to understand the relation between the length and amino acid composition of the luminal KASH domain, and the function of the SUN–KASH complex. We show that longer KASH domains can withstand and transfer higher forces and interact with the membrane through a conserved membrane proximal EEDY domain that is unique to longer KASH domains. In agreement with our models, our in vivo results show that swapping the KASH domains of ANC-1 and UNC-83, or shortening the KASH domain of ANC-1, both result in a nuclear anchorage defect in C. elegans.

View Accepted Manuscript (DOE)

Research Organization:: Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)

Sponsoring Organization:: National Institutes of Health (NIH); National Science Foundation (NSF); USDOE Office of Science (SC)

Grant/Contract Number:: AC02-05CH11231

OSTI ID:: 1633237

Journal Information:: Molecular Biology of the Cell, Journal Name: Molecular Biology of the Cell Journal Issue: 16 Vol. 30; ISSN 1059-1524

Publisher:: American Society for Cell BiologyCopyright Statement

Country of Publication:: United States

Language:: English

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