Interfacial binding and aggregation of lamin A tail domains associated with Hutchinson–Gilford progeria syndrome
Hutchinson–Gilford progeria syndrome is a premature aging disorder associated with the expression of ∆50 lamin A (∆50LA), a mutant form of the nuclear structural protein lamin A (LA). ∆50LA is missing 50 amino acids from the tail domain and retains a C-terminal farnesyl group that is cleaved from th...
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| Format: | Article |
| Language: | en_US |
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Elsevier
2017
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| Online Access: | http://hdl.handle.net/1721.1/108675 https://orcid.org/0000-0002-4173-9659 |
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| author | Kalinowski, Agnieszka Yaron, Peter N. Qin, Zhao Shenoy, Siddharth Dahl, Kris Noel Buehler, Markus J Loesche, 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 Yaron, Peter N. Qin, Zhao Shenoy, Siddharth Dahl, Kris Noel Buehler, Markus J Loesche, Mathias |
| author_sort | Kalinowski, Agnieszka |
| collection | MIT |
| description | Hutchinson–Gilford progeria syndrome is a premature aging disorder associated with the expression of ∆50 lamin A (∆50LA), a mutant form of the nuclear structural protein lamin A (LA). ∆50LA is missing 50 amino acids from the tail domain and retains a C-terminal farnesyl group that is cleaved from the wild-type LA. Many of the cellular pathologies of HGPS are thought to be a consequence of protein–membrane association mediated by the retained farnesyl group. To better characterize the protein–membrane interface, we quantified binding of purified recombinant ∆50LA tail domain (∆50LA-TD) to tethered bilayer membranes composed of phosphatidylserine and phosphocholine using surface plasmon resonance. Farnesylated ∆50LA-TD binds to the membrane interface only in the presence of Ca[superscript 2 +] or Mg[superscript 2 +] at physiological ionic strength. At extremely low ionic strength, both the farnesylated and non-farnesylated forms of ∆50LA-TD bind to the membrane surface in amounts that exceed those expected for a densely packed protein monolayer. Interestingly, the wild-type LA-TD with no farnesylation also associates with membranes at low ionic strength but forms only a single layer. We suggest that electrostatic interactions are mediated by charge clusters with a net positive charge that we calculate on the surface of the LA-TDs. These studies suggest that the accumulation of ∆50LA at the inner nuclear membrane observed in cells is due to a combination of aggregation and membrane association rather than simple membrane binding; electrostatics plays an important role in mediating this association. |
| first_indexed | 2024-09-23T16:13:05Z |
| format | Article |
| id | mit-1721.1/108675 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T16:13:05Z |
| publishDate | 2017 |
| publisher | Elsevier |
| record_format | dspace |
| spelling | mit-1721.1/1086752022-09-29T19:00:57Z Interfacial binding and aggregation of lamin A tail domains associated with Hutchinson–Gilford progeria syndrome Kalinowski, Agnieszka Yaron, Peter N. Qin, Zhao Shenoy, Siddharth Dahl, Kris Noel Buehler, Markus J Loesche, Mathias Massachusetts Institute of Technology. Department of Civil and Environmental Engineering Buehler, Markus J Loesche, Mathias Hutchinson–Gilford progeria syndrome is a premature aging disorder associated with the expression of ∆50 lamin A (∆50LA), a mutant form of the nuclear structural protein lamin A (LA). ∆50LA is missing 50 amino acids from the tail domain and retains a C-terminal farnesyl group that is cleaved from the wild-type LA. Many of the cellular pathologies of HGPS are thought to be a consequence of protein–membrane association mediated by the retained farnesyl group. To better characterize the protein–membrane interface, we quantified binding of purified recombinant ∆50LA tail domain (∆50LA-TD) to tethered bilayer membranes composed of phosphatidylserine and phosphocholine using surface plasmon resonance. Farnesylated ∆50LA-TD binds to the membrane interface only in the presence of Ca[superscript 2 +] or Mg[superscript 2 +] at physiological ionic strength. At extremely low ionic strength, both the farnesylated and non-farnesylated forms of ∆50LA-TD bind to the membrane surface in amounts that exceed those expected for a densely packed protein monolayer. Interestingly, the wild-type LA-TD with no farnesylation also associates with membranes at low ionic strength but forms only a single layer. We suggest that electrostatic interactions are mediated by charge clusters with a net positive charge that we calculate on the surface of the LA-TDs. These studies suggest that the accumulation of ∆50LA at the inner nuclear membrane observed in cells is due to a combination of aggregation and membrane association rather than simple membrane binding; electrostatics plays an important role in mediating this association. National Institute of General Medical Sciences (U.S.) (1R01-GM101647) United States. Office of Naval Research. Presidential Early Career Award for Scientists and Engineers (N000141010562) National Institutes of Health (U.S.) (U01 EB014976) 2017-05-04T20:16:49Z 2017-05-04T20:16:49Z 2014-08 2014-07 Article http://purl.org/eprint/type/JournalArticle 03014622 http://hdl.handle.net/1721.1/108675 Kalinowski, Agnieszka et al. “Interfacial Binding and Aggregation of Lamin A Tail Domains Associated with Hutchinson–Gilford Progeria Syndrome.” Biophysical Chemistry 195 (2014): 43–48. https://orcid.org/0000-0002-4173-9659 en_US http://dx.doi.org/10.1016/j.bpc.2014.08.005 Biophysical Chemistry Creative Commons Attribution-NonCommercial-NoDerivs License http://creativecommons.org/licenses/by-nc-nd/4.0/ application/pdf Elsevier PMC |
| spellingShingle | Kalinowski, Agnieszka Yaron, Peter N. Qin, Zhao Shenoy, Siddharth Dahl, Kris Noel Buehler, Markus J Loesche, Mathias Interfacial binding and aggregation of lamin A tail domains associated with Hutchinson–Gilford progeria syndrome |
| title | Interfacial binding and aggregation of lamin A tail domains associated with Hutchinson–Gilford progeria syndrome |
| title_full | Interfacial binding and aggregation of lamin A tail domains associated with Hutchinson–Gilford progeria syndrome |
| title_fullStr | Interfacial binding and aggregation of lamin A tail domains associated with Hutchinson–Gilford progeria syndrome |
| title_full_unstemmed | Interfacial binding and aggregation of lamin A tail domains associated with Hutchinson–Gilford progeria syndrome |
| title_short | Interfacial binding and aggregation of lamin A tail domains associated with Hutchinson–Gilford progeria syndrome |
| title_sort | interfacial binding and aggregation of lamin a tail domains associated with hutchinson gilford progeria syndrome |
| url | http://hdl.handle.net/1721.1/108675 https://orcid.org/0000-0002-4173-9659 |
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