Calcium Causes a Conformational Change in Lamin A Tail Domain that Promotes Farnesyl-Mediated Membrane Association
Lamin proteins contribute to nuclear structure and function, primarily at the inner nuclear membrane. The posttranslational processing pathway of lamin A includes farnesylation of the C-terminus, likely to increase membrane association, and subsequent proteolytic cleavage of the C-terminus. Hutchins...
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| Format: | Article |
| Language: | en_US |
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Elsevier
2014
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| Online Access: | http://hdl.handle.net/1721.1/89214 https://orcid.org/0000-0002-4173-9659 |
| _version_ | 1826195054356594688 |
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| author | Kalinowski, Agnieszka Qin, Zhao Coffey, Kelli Kodali, Ravi Buehler, Markus J. Dahl, Kris Noel Losche, Mathias |
| author2 | Massachusetts Institute of Technology. Department of Civil and Environmental Engineering |
| author_facet | Massachusetts Institute of Technology. Department of Civil and Environmental Engineering Kalinowski, Agnieszka Qin, Zhao Coffey, Kelli Kodali, Ravi Buehler, Markus J. Dahl, Kris Noel Losche, Mathias |
| author_sort | Kalinowski, Agnieszka |
| collection | MIT |
| description | Lamin proteins contribute to nuclear structure and function, primarily at the inner nuclear membrane. The posttranslational processing pathway of lamin A includes farnesylation of the C-terminus, likely to increase membrane association, and subsequent proteolytic cleavage of the C-terminus. Hutchinson Gilford progeria syndrome is a premature aging disorder wherein a mutant version of lamin A, Δ50 lamin A, retains its farnesylation. We report here that membrane association of farnesylated Δ50 lamin A tail domains requires calcium. Experimental evidence and molecular dynamics simulations collectively suggest that the farnesyl group is sequestered within a hydrophobic region in the tail domain in the absence of calcium. Calcium binds to the tail domain with an affinity K[subscript D] ≈ 250 μM where it alters the structure of the Ig-fold and increases the solvent accessibility of the C-terminus. In 2 mM CaCl[subscript 2], the affinity of the farnesylated protein to a synthetic membrane is K[subscript D] ≈ 2 μM, as measured with surface plasmon resonance, but showed a combination of aggregation and binding. Membrane binding in the absence of calcium could not be detected. We suggest that a conformational change induced in Δ50 lamin A with divalent cations plays a regulatory role in the posttranslational processing of lamin A, which may be important in disease pathogenesis. |
| first_indexed | 2024-09-23T10:06:31Z |
| format | Article |
| id | mit-1721.1/89214 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T10:06:31Z |
| publishDate | 2014 |
| publisher | Elsevier |
| record_format | dspace |
| spelling | mit-1721.1/892142022-09-26T15:43:58Z Calcium Causes a Conformational Change in Lamin A Tail Domain that Promotes Farnesyl-Mediated Membrane Association Kalinowski, Agnieszka Qin, Zhao Coffey, Kelli Kodali, Ravi Buehler, Markus J. Dahl, Kris Noel Losche, Mathias Massachusetts Institute of Technology. Department of Civil and Environmental Engineering Massachusetts Institute of Technology. School of Engineering Qin, Zhao Buehler, Markus J. Lamin proteins contribute to nuclear structure and function, primarily at the inner nuclear membrane. The posttranslational processing pathway of lamin A includes farnesylation of the C-terminus, likely to increase membrane association, and subsequent proteolytic cleavage of the C-terminus. Hutchinson Gilford progeria syndrome is a premature aging disorder wherein a mutant version of lamin A, Δ50 lamin A, retains its farnesylation. We report here that membrane association of farnesylated Δ50 lamin A tail domains requires calcium. Experimental evidence and molecular dynamics simulations collectively suggest that the farnesyl group is sequestered within a hydrophobic region in the tail domain in the absence of calcium. Calcium binds to the tail domain with an affinity K[subscript D] ≈ 250 μM where it alters the structure of the Ig-fold and increases the solvent accessibility of the C-terminus. In 2 mM CaCl[subscript 2], the affinity of the farnesylated protein to a synthetic membrane is K[subscript D] ≈ 2 μM, as measured with surface plasmon resonance, but showed a combination of aggregation and binding. Membrane binding in the absence of calcium could not be detected. We suggest that a conformational change induced in Δ50 lamin A with divalent cations plays a regulatory role in the posttranslational processing of lamin A, which may be important in disease pathogenesis. National Science Foundation (U.S.) (CMMI-0642545) United States. Office of Naval Research. Presidential Early Career Award for Scientists and Engineers (N00014-10-1-0562) 2014-09-05T18:53:57Z 2014-09-05T18:53:57Z 2013-05 2012-11 Article http://purl.org/eprint/type/JournalArticle 00063495 1542-0086 http://hdl.handle.net/1721.1/89214 Kalinowski, Agnieszka, Zhao Qin, Kelli Coffey, Ravi Kodali, Markus J. Buehler, Mathias Losche, and Kris Noel Dahl. “Calcium Causes a Conformational Change in Lamin A Tail Domain That Promotes Farnesyl-Mediated Membrane Association.” Biophysical Journal 104, no. 10 (May 2013): 2246–2253. © 2013 Biophysical Society https://orcid.org/0000-0002-4173-9659 en_US http://dx.doi.org/10.1016/j.bpj.2013.04.016 Biophysical Journal Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use. application/pdf Elsevier Elsevier Open Archive |
| spellingShingle | Kalinowski, Agnieszka Qin, Zhao Coffey, Kelli Kodali, Ravi Buehler, Markus J. Dahl, Kris Noel Losche, Mathias Calcium Causes a Conformational Change in Lamin A Tail Domain that Promotes Farnesyl-Mediated Membrane Association |
| title | Calcium Causes a Conformational Change in Lamin A Tail Domain that Promotes Farnesyl-Mediated Membrane Association |
| title_full | Calcium Causes a Conformational Change in Lamin A Tail Domain that Promotes Farnesyl-Mediated Membrane Association |
| title_fullStr | Calcium Causes a Conformational Change in Lamin A Tail Domain that Promotes Farnesyl-Mediated Membrane Association |
| title_full_unstemmed | Calcium Causes a Conformational Change in Lamin A Tail Domain that Promotes Farnesyl-Mediated Membrane Association |
| title_short | Calcium Causes a Conformational Change in Lamin A Tail Domain that Promotes Farnesyl-Mediated Membrane Association |
| title_sort | calcium causes a conformational change in lamin a tail domain that promotes farnesyl mediated membrane association |
| url | http://hdl.handle.net/1721.1/89214 https://orcid.org/0000-0002-4173-9659 |
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