{"201001":{"#nid":"201001","#data":{"type":"news","title":"Mechanical Forces Control Assembly and Disassembly of a Key Cell Protein","body":[{"value":"\u003Cp\u003EResearchers have for the first time demonstrated that mechanical forces can control the depolymerization of actin, a critical protein that provides the major force-bearing structure in the cytoskeletons of cells. The research suggests that forces applied both externally and internally may play a much larger role than previously believed in regulating a range of processes inside cells.\u003C\/p\u003E\u003Cp\u003EUsing atomic force microscopy (AFM) force-clamp experiments, the research found that tensile force regulates the kinetics of actin dissociation by prolonging the lifetimes of bonds at low force range, and by shortening bond lifetimes beyond a force threshold. The research also identified a possible molecular basis for the bonds that form when mechanical forces create new interactions between subunits of actin.\u003C\/p\u003E\u003Cp\u003EFound in the cytoskeleton of nearly all cells, actin forms dynamic microfilaments that provide structure and sustain forces. A cell\u2019s ability to assemble and disassemble actin allows it to rapidly move or change shape in response to the environment.\u003C\/p\u003E\u003Cp\u003EThe research was reported March 4 in the early online edition of the journal \u003Cem\u003EProceedings of the National Academy of Sciences\u003C\/em\u003E (PNAS). The work was supported by the National Institutes of Health (NIH).\u003C\/p\u003E\u003Cp\u003E\u201cFor the first time, we have shown that mechanical force can directly regulate how actin is assembled and disassembled,\u201d said \u003Ca href=\u0022http:\/\/www.bme.gatech.edu\/facultystaff\/faculty_record.php?id=56\u0022\u003ELarry McIntire\u003C\/a\u003E, chair of the \u003Ca href=\u0022http:\/\/www.bme.gatech.edu\/\u0022\u003EWallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory University\u003C\/a\u003E and corresponding author of the study. \u201cActin is fundamental to how cells accomplish most of their functions and processes. This research gives us a whole new way of thinking about how a cell can do things like rearrange its cytoskeleton in response to external forces.\u201d\u003C\/p\u003E\u003Cp\u003EThe external forces affecting a cell could arise from such mechanical actions as blood flow, trauma to the body, or the loading of bones and other tissue as organisms move around.\u003C\/p\u003E\u003Cp\u003E\u201cForces are applied to cells all the time, and often they are directional, not uniformly applied in a certain direction,\u201d said McIntire. \u201cThe cell can rearrange its cytoskeleton to either accommodate the forces that are being applied, or apply its own forces to do something \u2013 such as moving to go after food.\u201d\u003C\/p\u003E\u003Cp\u003EBecause these forces regulate the polymerization and depolymerization of actin, they load the actin fibers in a specific direction, affecting the duration of bonds that may influence cellular growth in one direction, he said.\u003C\/p\u003E\u003Cp\u003EFor instance, tensile forces applied to the actin produce catch bonds, in which the bond lifetime increases as the force increases. These catch bonds have been shown to exist in other proteins, but actin is the most important protein known to form the structures. Most bonds at the cellular level are slip bonds which, unlike catch bonds, dissociate more quickly with application of force.\u003C\/p\u003E\u003Cp\u003EThe researchers used a specially-constructed AFM to conduct their experiments. The tip was coated with actin monomers, while a polystyrene surface below the AFM tip was coated with either monomeric or filamentous actin. To study the catch-slip bonds, the tip was driven close to the surface to allow bond formation, then retracted to pull on the bond. The tension was held stationary to measure the bond lifetime at a constant force.\u003C\/p\u003E\u003Cp\u003EThe research team also used molecular dynamics simulations to predict the specific amino acids likely to be important in forming the catch bonds. Experiments using specialized reagents confirmed the molecular mechanism, a lysine-glutamic acid-salt bridge believed to be responsible for forming long-lived bonds between actin sub-units when force is applied to them.\u003C\/p\u003E\u003Cp\u003E\u201cWhat we found was that when you apply force, the force induces additional interactions at the atomic scale,\u201d said \u003Ca href=\u0022http:\/\/www.bme.gatech.edu\/facultystaff\/faculty_record.php?id=4\u0022\u003ECheng Zhu\u003C\/a\u003E, a Regents\u2019 professor in the Coulter Department of Biomedical Engineering and co-corresponding author of the paper. \u201cWhen you apply force, you find that residues that had previously not been making contact are now interacting. These are force-induced interactions.\u201d\u003C\/p\u003E\u003Cp\u003EProof that force application can play a role in the internal functions of cells demonstrates the growing importance of a relatively new field of research known as mechano-biology, which studies how mechanical activities affect living tissues.\u003C\/p\u003E\u003Cp\u003E\u201cWe know that the cell can sense the mechanical environment around it,\u201d said Zhu, who holds the J. Erskine Love Endowed Chair in Engineering. \u201cOne of the cell\u2019s responses to the mechanical environment is to change shape and reorganize the actin cytoskeleton. Previously, it was thought that sensory molecules at the cell surface were required to convert the mechanical cues into biochemical signals before the actin cytoskeleton could be altered. The mechanism we describe can bypass the cellular signaling mechanisms because actin bears the force in the cell.\u201d\u003C\/p\u003E\u003Cp\u003EThe work sets the stage for additional research into other biochemical reactions that may be produced by the application of force.\u003C\/p\u003E\u003Cp\u003E\u201cIt\u2019s becoming more and more clear that the ability of the cell to vary its mechanical environment, in addition to responding to what\u2019s going on outside it, is crucial to a lot of what goes on with the biochemistry in the cell functions,\u201d McIntire added. \u201cIf you can change the structure of the amino acids by pulling on them, and that force is applied to an enzymatic site, you can increase or decrease the enzymatic activity by changing the local structure of the amino acids.\u201d\u003C\/p\u003E\u003Cp\u003EThe research was inspired by a 2005 paper from the Shu Chien lab at the University of California at San Diego, and was carried out by Georgia Tech graduate student Cho-yin Lee (now at the National Taiwan University Hospital) and research scientist Jizhong Lou (now at the Chinese Academy of Sciences), with intellectual input from Suzanne B. Eskin from Georgia Tech and Shoichiro Ono from Emory University.\u0026nbsp; Kuo-kuang Wen and Melissa McKane from the laboratory of Peter A. Rubenstein at the University of Iowa provided actin mutants used in the research.\u003C\/p\u003E\u003Cp\u003E\u003Cem\u003EThis research was supported by the National Institutes of Health (NIH) under grants HL18672, HL70537, HL091020, HL093723, AI077343, AI044902, AR48615 and DC8803, and by the National Natural Science Foundation of China grants 31070827, 31222022 and 81161120424. The conclusions are those of the principal investigators and do not necessarily represent the official views of the NIH.\u003C\/em\u003E\u003C\/p\u003E\u003Cp\u003E\u003Cstrong\u003ECITATION\u003C\/strong\u003E: Lee, Cho-Yin, et. al., \u201cActin depolymerization under force is governed by lysine 113:glutamic acid 195-mediated catch-slip bonds,\u201d (Proceedings of the National Academy of Sciences, 2013). \u003Ca href=\u0022http:\/\/www.pnas.org\/content\/early\/2013\/03\/01\/1218407110\u0022 title=\u0022http:\/\/www.pnas.org\/content\/early\/2013\/03\/01\/1218407110\u0022\u003Ehttp:\/\/www.pnas.org\/content\/early\/2013\/03\/01\/1218407110\u003C\/a\u003E\u003C\/p\u003E\u003Cp\u003E\u003Cbr \/\u003E\u003Cstrong\u003EResearch News\u003C\/strong\u003E\u003Cbr \/\u003E\u003Cstrong\u003EGeorgia Institute of Technology\u003C\/strong\u003E\u003Cbr \/\u003E\u003Cstrong\u003E177 North Avenue\u003C\/strong\u003E\u003Cbr \/\u003E\u003Cstrong\u003EAtlanta, Georgia\u0026nbsp; 30332-0181\u003C\/strong\u003E\u003Cbr \/\u003E\u003Cbr \/\u003E\u003Cstrong\u003EMedia Relations Contact\u003C\/strong\u003E: John Toon (404-894-6986)(\u003Ca href=\u0022mailto:jtoon@gatech.edu\u0022\u003Ejtoon@gatech.edu\u003C\/a\u003E).\u003C\/p\u003E\u003Cp\u003E\u003Cstrong\u003EWriter\u003C\/strong\u003E: John Toon\u003C\/p\u003E","summary":null,"format":"limited_html"}],"field_subtitle":"","field_summary":[{"value":"\u003Cp\u003EResearchers have for the first time demonstrated that mechanical forces can control the depolymerization of actin, a critical protein that provides the major force-bearing structure in the cytoskeletons of cells. The research suggests that forces applied both externally and internally may play a much larger role than previously believed in regulating a range of processes inside cells.\u003C\/p\u003E","format":"limited_html"}],"field_summary_sentence":[{"value":"A new study suggests that mechanical forces may play a much larger role in regulating cellular processes."}],"uid":"27303","created_gmt":"2013-03-20 14:48:37","changed_gmt":"2016-10-08 03:13:51","author":"John Toon","boilerplate_text":"","field_publication":"","field_article_url":"","dateline":{"date":"2013-03-20T00:00:00-04:00","iso_date":"2013-03-20T00:00:00-04:00","tz":"America\/New_York"},"extras":[],"hg_media":{"200951":{"id":"200951","type":"image","title":"AFM Cantilever for Actin Study","body":null,"created":"1449179943","gmt_created":"2015-12-03 21:59:03","changed":"1475894853","gmt_changed":"2016-10-08 02:47:33","alt":"AFM Cantilever for Actin Study","file":{"fid":"196569","name":"afm-cantilever.jpg","image_path":"\/sites\/default\/files\/images\/afm-cantilever_0.jpg","image_full_path":"http:\/\/hg.gatech.edu\/\/sites\/default\/files\/images\/afm-cantilever_0.jpg","mime":"image\/jpeg","size":823628,"path_740":"http:\/\/hg.gatech.edu\/sites\/default\/files\/styles\/740xx_scale\/public\/images\/afm-cantilever_0.jpg?itok=_nsaKLZb"}},"200971":{"id":"200971","type":"image","title":"Protein Progression in Actin","body":null,"created":"1449179943","gmt_created":"2015-12-03 21:59:03","changed":"1475894853","gmt_changed":"2016-10-08 02:47:33","alt":"Protein Progression in Actin","file":{"fid":"196570","name":"protein-progression.jpg","image_path":"\/sites\/default\/files\/images\/protein-progression_0.jpg","image_full_path":"http:\/\/hg.gatech.edu\/\/sites\/default\/files\/images\/protein-progression_0.jpg","mime":"image\/jpeg","size":1311519,"path_740":"http:\/\/hg.gatech.edu\/sites\/default\/files\/styles\/740xx_scale\/public\/images\/protein-progression_0.jpg?itok=uW_bbCkd"}}},"media_ids":["200951","200971"],"groups":[{"id":"1188","name":"Research Horizons"}],"categories":[{"id":"146","name":"Life Sciences and Biology"}],"keywords":[{"id":"28591","name":"Actin"},{"id":"532","name":"cell"},{"id":"9893","name":"Cheng Zhu"},{"id":"14219","name":"Coulter Department of Biomedical Engineering"},{"id":"62091","name":"cytoskeleton"},{"id":"62111","name":"depolymerization"},{"id":"14772","name":"Larry McIntire"},{"id":"62101","name":"mechanical force"},{"id":"3003","name":"protein"}],"core_research_areas":[{"id":"39441","name":"Bioengineering and Bioscience"}],"news_room_topics":[],"event_categories":[],"invited_audience":[],"affiliations":[],"classification":[],"areas_of_expertise":[],"news_and_recent_appearances":[],"phone":[],"contact":[{"value":"\u003Cp\u003EJohn Toon\u003C\/p\u003E\u003Cp\u003EResearch News\u003C\/p\u003E\u003Cp\u003E\u003Ca href=\u0022mailto:jtoon@gatech.edu\u0022\u003Ejtoon@gatech.edu\u003C\/a\u003E\u003C\/p\u003E\u003Cp\u003E(404) 894-6986\u003C\/p\u003E","format":"limited_html"}],"email":["jtoon@gatech.edu"],"slides":[],"orientation":[],"userdata":""}}}