Conserved SUN-KASH Interfaces Mediate LINC Complex-Dependent Nuclear Movement and Positioning
| Autor: | Nathan J. Harris, Amy Schoenhofen, Baila Elkin, Natalie E. Cain, Brian M. Woolums, Hongyan Hao, Daniel A. Starr, Zeinab Jahed, Venecia A. Valdez, Leslie A Herrera, G. W. Gant Luxton, Mohammad R. K. Mofrad |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
LINC complex Cell Cycle Proteins medicine.disease_cause Microtubules Medical and Health Sciences Mice Cytoskeleton Mutation Intracellular Signaling Peptides and Proteins Nuclear Proteins Biological Sciences Cell biology Protein Transport Generic Health Relevance General Agricultural and Biological Sciences Protein Structure SUN proteins Nuclear Envelope nuclear positioning 1.1 Normal biological development and functioning In silico Biology Article General Biochemistry Genetics and Molecular Biology 03 medical and health sciences Underpinning research medicine Animals Inner membrane Nuclear Matrix Amino Acid Sequence Caenorhabditis elegans Caenorhabditis elegans Proteins Cell Nucleus Nesprin KASH proteins Psychology and Cognitive Sciences Membrane Proteins Biological Transport Protein Structure Tertiary 030104 developmental biology NIH 3T3 Cells Tertiary Function (biology) Developmental Biology Cysteine |
| Zdroj: | Current biology : CB, vol 28, iss 19 Cain, NE; Jahed, Z; Schoenhofen, A; Valdez, VA; Elkin, B; Hao, H; et al.(2018). Conserved SUN-KASH Interfaces Mediate LINC Complex-Dependent Nuclear Movement and Positioning. Current Biology, 28(19), 3086-3097.e4. doi: 10.1016/j.cub.2018.08.001. UC Berkeley: Retrieved from: http://www.escholarship.org/uc/item/4d50b0dp |
| ISSN: | 0960-9822 |
| DOI: | 10.1016/j.cub.2018.08.001 |
| Popis: | © 2018 Elsevier Ltd Many nuclear positioning events involve linker of nucleoskeleton and cytoskeleton (LINC) complexes, which transmit forces generated by the cytoskeleton across the nuclear envelope. LINC complexes are formed by trans-luminal interactions between inner nuclear membrane SUN proteins and outer nuclear membrane KASH proteins, but how these interactions are regulated is poorly understood. We combine in vivo C. elegans genetics, in vitro wounded fibroblast polarization, and in silico molecular dynamics simulations to elucidate mechanisms of LINC complexes. The extension of the KASH domain by a single alanine residue or the mutation of the conserved tyrosine at −7 completely blocked the nuclear migration function of C. elegans UNC-83. Analogous mutations at −7 of mouse nesprin-2 disrupted rearward nuclear movements in NIH 3T3 cells, but did not disrupt ANC-1 in nuclear anchorage. Furthermore, conserved cysteines predicted to form a disulfide bond between SUN and KASH proteins are important for the function of certain LINC complexes, and might promote a developmental switch between nuclear migration and nuclear anchorage. Mutations of conserved cysteines in SUN or KASH disrupted ANC-1-dependent nuclear anchorage in C. elegans and Nesprin-2G-dependent nuclear movements in polarizing fibroblasts. However, the SUN cysteine mutation did not disrupt nuclear migration. Moreover, molecular dynamics simulations showed that a disulfide bond is necessary for the maximal transmission of cytoskeleton-generated forces by LINC complexes in silico. Thus, we have demonstrated functions for SUN-KASH binding interfaces, including a predicted intermolecular disulfide bond, as mechanistic determinants of nuclear positioning that may represent targets for regulation. Cain et al. test the function of mutant SUN and KASH proteins in C. elegans nuclear positioning, NIH 3T3 fibroblast polarization, and simulations of LINC complexes under mechanical strain to gain mechanistic insights into how SUN-KASH interactions might be regulated to transfer forces from the cytoskeleton to the nucleus. |
| Databáze: | OpenAIRE |
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