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Title: Molecular Insights into the Mechanisms of SUN1 Oligomerization in the Nuclear Envelope

Abstract

The LINC complex is found in a wide variety of organisms and is formed by the transluminal interaction betweenouter- and inner-nuclear-membrane KASH and SUN proteins, respectively. Most extensively studied are SUN1 and SUN2 pro-teins, which are widely expressed in mammals. Although SUN1 and SUN2 play functionally redundant roles in several cellularprocesses, more recent studies have revealed diverse and distinct functions for SUN1. While several recent in vitro structuralstudies have revealed the molecular details of various fragments of SUN2, no such structural information is available for SUN1.Herein, we conduct a systematic analysis of the molecular relationships between SUN1 and SUN2, highlighting key similaritiesand differences that could lead to clues into their distinct functions. We use a wide range of computational tools, including mul-tiple sequence alignments, homology modeling, molecular docking, and molecular dynamic simulations, to predict structural dif-ferences between SUN1 and SUN2, with the goal of understanding the molecular mechanisms underlying SUN1 oligomerizationin the nuclear envelope. Our simulations suggest that the structural model of SUN1 is stable in a trimeric state and that SUN1trimers can associate through their SUN domains to form lateral complexes. We also ask whether SUN1 could adopt an inactivemonomeric conformation as seen in SUN2. Our results imply thatmore » the KASH binding domain of SUN1 is also inhibited in mono-meric SUN1 but through weaker interactions than in monomeric SUN2.« less

Authors:
 [1];  [1];  [1];  [1];  [2];  [3]
  1. University of California Berkeley, Berkeley, CA (United States). Molecular Cell Biomechanics Laboratory, Departments of Bioengineering and Mechanical Engineering
  2. University of Minnesota, Minneapolis, MN (United States). Department of Genetics, Cell Biology, and Development
  3. University of California Berkeley, Berkeley, CA (United States). Molecular Cell Biomechanics Laboratory, Departments of Bioengineering and Mechanical Engineering; Lawrence Berkeley National Laboratory. (LBNL), Berkeley, CA (United States). Molecular Biophysics and Integrated Bioimaging Division
Publication Date:
Research Org.:
Lawrence Berkeley National Laboratory, Berkeley, CA (United States). National Energy Research Scientific Computing Center (NERSC).
Sponsoring Org.:
USDOE Office of Science (SC), Advanced Scientific Computing Research (ASCR) (SC-21)
OSTI Identifier:
1462512
DOE Contract Number:  
AC02-05CH11231
Resource Type:
Journal Article
Journal Name:
Biophysical Journal
Additional Journal Information:
Journal Volume: 114; Journal Issue: 5; Journal ID: ISSN 0006-3495
Country of Publication:
United States
Language:
English

Citation Formats

Jahed, Zeinab, Fadavi, Darya, Vu, Uyen T., Asgari, Ehsaneddin, Luxton, G. W. Gant, and Mofrad, Mohammad R. K. Molecular Insights into the Mechanisms of SUN1 Oligomerization in the Nuclear Envelope. United States: N. p., 2018. Web. doi:10.1016/j.bpj.2018.01.015.
Jahed, Zeinab, Fadavi, Darya, Vu, Uyen T., Asgari, Ehsaneddin, Luxton, G. W. Gant, & Mofrad, Mohammad R. K. Molecular Insights into the Mechanisms of SUN1 Oligomerization in the Nuclear Envelope. United States. doi:10.1016/j.bpj.2018.01.015.
Jahed, Zeinab, Fadavi, Darya, Vu, Uyen T., Asgari, Ehsaneddin, Luxton, G. W. Gant, and Mofrad, Mohammad R. K. Thu . "Molecular Insights into the Mechanisms of SUN1 Oligomerization in the Nuclear Envelope". United States. doi:10.1016/j.bpj.2018.01.015.
@article{osti_1462512,
title = {Molecular Insights into the Mechanisms of SUN1 Oligomerization in the Nuclear Envelope},
author = {Jahed, Zeinab and Fadavi, Darya and Vu, Uyen T. and Asgari, Ehsaneddin and Luxton, G. W. Gant and Mofrad, Mohammad R. K.},
abstractNote = {The LINC complex is found in a wide variety of organisms and is formed by the transluminal interaction betweenouter- and inner-nuclear-membrane KASH and SUN proteins, respectively. Most extensively studied are SUN1 and SUN2 pro-teins, which are widely expressed in mammals. Although SUN1 and SUN2 play functionally redundant roles in several cellularprocesses, more recent studies have revealed diverse and distinct functions for SUN1. While several recent in vitro structuralstudies have revealed the molecular details of various fragments of SUN2, no such structural information is available for SUN1.Herein, we conduct a systematic analysis of the molecular relationships between SUN1 and SUN2, highlighting key similaritiesand differences that could lead to clues into their distinct functions. We use a wide range of computational tools, including mul-tiple sequence alignments, homology modeling, molecular docking, and molecular dynamic simulations, to predict structural dif-ferences between SUN1 and SUN2, with the goal of understanding the molecular mechanisms underlying SUN1 oligomerizationin the nuclear envelope. Our simulations suggest that the structural model of SUN1 is stable in a trimeric state and that SUN1trimers can associate through their SUN domains to form lateral complexes. We also ask whether SUN1 could adopt an inactivemonomeric conformation as seen in SUN2. Our results imply that the KASH binding domain of SUN1 is also inhibited in mono-meric SUN1 but through weaker interactions than in monomeric SUN2.},
doi = {10.1016/j.bpj.2018.01.015},
journal = {Biophysical Journal},
issn = {0006-3495},
number = 5,
volume = 114,
place = {United States},
year = {2018},
month = {3}
}