Pathogenic peptide deviations support a model of adaptive evolution of chordate cardiac performance by troponin mutations

Physiological Genomics - Tập 42 Số 2 - Trang 287-299 - 2010
Nathan J. Palpant1, Evelyne M. Houang2, Wayne Delport3, Kenneth E.M. Hastings4, Alexey V. Onufriev5, Yuk Y. Sham2, Joseph M. Metzger1
1Department of Integrative Biology and Physiology and
2Center for Drug Design, University of Minnesota Academic Health Center, Minneapolis, Minnesota
3Antiviral Research Center, Department of Medicine, University of California, San Diego, California;
4Montreal Neurological Institute and Department of Biology, McGill University, Montreal, Quebec, Canada; and
5Departments of Computer Science and Physics, Virginia Polytechnic Institute and State University, Blacksburg, Virginia

Tóm tắt

In cardiac muscle, the troponin (cTn) complex is a key regulator of myofilament calcium sensitivity because it serves as a molecular switch required for translating myocyte calcium fluxes into sarcomeric contraction and relaxation. Studies of several species suggest that ectotherm chordates have myofilaments with heightened calcium responsiveness. However, genetic polymorphisms in cTn that cause increased myofilament sensitivity to activating calcium in mammals result in cardiac disease including arrhythmias, diastolic dysfunction, and increased susceptibility to sudden cardiac death. We hypothesized that specific residue modifications in the regulatory arm of troponin I (TnI) were critical in mediating the observed decrease in myofilament calcium sensitivity within the mammalian taxa. We performed large-scale phylogenetic analysis, atomic resolution molecular dynamics simulations and modeling, and computational alanine scanning. This study provides evidence that a His to Ala substitution within mammalian cardiac TnI (cTnI) reduced the thermodynamic potential at the interface between cTnI and cardiac TnC (cTnC) in the calcium-saturated state by disrupting a strong intermolecular electrostatic interaction. This key residue modification reduced myofilament calcium sensitivity by making cTnI molecularly untethered from cTnC. To meet the requirements for refined mammalian adult cardiac performance, we propose that compensatory evolutionary pressures favored mutations that enhanced the relaxation properties of cTn by decreasing its sensitivity to activating calcium.

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Tài liệu tham khảo

10.1242/jeb.00184

10.1093/molbev/msn232

10.1152/ajpheart.00520.2005

Babu A, 1987, J Biol Chem, 262, 5815, 10.1016/S0021-9258(18)45648-7

10.1016/j.jmb.2009.11.002

10.1016/j.jmb.2007.10.062

10.1007/3-540-63827-X_66

10.1021/bi00496a010

Baudenbacher F, 2008, J Clin Invest, 118, 3893

10.1016/j.resp.2006.01.002

10.1196/annals.1341.002

10.1002/elps.11501401163

10.1021/bi035504z

10.1111/j.1365-201X.2004.01359.x

10.1161/CIRCRESAHA.109.196055

10.1152/ajpregu.1994.267.1.R62

10.1093/molbev/msg227

10.1074/jbc.C200419200

10.1016/j.yjmcc.2008.02.274

10.1161/01.RES.0000268412.34364.50

10.1529/biophysj.106.095406

10.1038/nm1346

10.1007/s00109-007-0181-6

10.1093/bib/bbn049

10.1006/dbio.1994.1265

10.1152/ajpheart.91506.2007

10.1063/1.470117

Fiset C, 2008, J Clin Invest, 118, 3845

10.1089/ars.2007.1704

10.1016/j.gep.2009.02.001

Fu JD, 2006, Sheng Li Xue Bao, 58, 95

10.1152/physiolgenomics.00007.2005

10.1152/physiolgenomics.00197.2007

10.1152/ajpregu.2000.279.5.R1707

10.1152/ajpcell.00339.2002

10.1016/S1095-6433(02)00046-6

10.1074/jbc.M407340200

10.1152/physrev.2000.80.2.853

10.1093/nar/gki464

10.1080/10635150390235520

10.1016/0014-5793(88)80073-5

10.1247/csf.22.205

10.1007/BF02338796

10.1002/humu.1143

Holroyde MJ, 1980, J Biol Chem, 255, 11688, 10.1016/S0021-9258(19)70187-2

10.1093/cvr/cvm113

10.1063/1.445869

10.1073/pnas.232565499

10.1073/pnas.202485799

Kortemme T, 2004, Sci STKE, 2004, l2, 10.1126/stke.2192004pl2

10.1093/molbev/msl051

10.1093/bioinformatics/btl474

10.1038/nature08324

10.1126/science.1100522

10.1016/j.yjmcc.2008.05.003

10.1016/j.cardiores.2004.12.022

10.1006/jmcc.2000.1392

10.1002/prot.20660

10.1021/bi9901679

10.1016/S0006-3495(01)75702-5

10.1152/physiolgenomics.00154.2007

10.1016/S1095-6433(99)00129-4

10.1021/jp973084f

10.1023/A:1006860104840

10.1002/prot.21657

10.1074/jbc.M201761200

McKean T, 2002, J Exp Biol, 205, 1725, 10.1242/jeb.205.12.1725

McKean T, 1997, J Exp Biol, 200, 2575, 10.1242/jeb.200.19.2575

10.1074/jbc.M212601200

10.1161/01.RES.0000110083.17024.60

10.1093/oxfordjournals.jbchem.a021940

10.1016/S0735-1097(96)00530-X

10.1021/bi9906120

10.1074/jbc.M702563200

10.1096/fj.08-121996

10.1093/cvr/cvn198

10.1016/j.yjmcc.2007.06.012

10.1002/jcc.20289

10.1074/jbc.M109.007021

10.1093/bioinformatics/bti320

10.1161/01.CIR.0000066323.15244.54

10.2307/1536959

10.1016/0021-9991(77)90098-5

10.1007/BF01739858

10.1111/j.1742-4658.2005.05001.x

10.1016/S0008-6363(03)00255-4

Sheng HZ, 2008, Zhonghua Xin Xue Guan Bing Za Zhi, 36, 1063

10.1085/jgp.200609543

10.1242/jeb.003145

10.1152/ajpregu.00510.2004

10.1113/jphysiol.2002.036509

10.1016/j.cbpc.2008.05.016

10.1080/03610927808827599

10.1042/bj1530375

10.1038/nature01780

10.1161/01.RES.0000117307.57798.F5

10.1172/JCI6067

10.1016/0092-8674(94)90054-X

10.1093/nar/22.22.4673

10.1074/jbc.M201768200

10.1161/CIRCULATIONAHA.107.755777

10.1161/01.RES.0000173849.68636.1e

10.1073/pnas.0408882102

10.1002/dvdy.10434

10.1016/S0925-4773(02)00096-5

10.1074/jbc.M801661200

10.1074/jbc.274.32.22508

10.1161/01.RES.86.4.470

10.1161/01.RES.0000034710.46739.C0

10.1007/978-1-4419-9029-7_15

10.1016/j.yjmcc.2007.05.017

10.1073/pnas.94.10.5444

10.1111/j.1469-7793.2001.00863.x

10.1074/jbc.M808075200

10.1017/S0016672308009816

10.1006/jmbi.1993.1294

10.1161/CIRCRESAHA.106.145557

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Physiological Genomics

Tập 42 Số 2

287-299

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