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Familial hypertrophic cardiomyopathy (FHC) is the most common cause of sudden cardiac death in young individuals. Molecular mechanisms underlying this disorder are largely unknown; this study aims at revealing how disruptions in actin-myosin interactions can play a role in this disorder. Cross-bridge (XB) kinetics and the degree of order were examined in contracting myofibrils from the ex vivo left ventricles of transgenic (Tg) mice expressing FHC regulatory light chain (RLC) mutation K104E. Because the degree of order and the kinetics are best studied when an individual XB makes a significant contribution to the overall signal, the number of observed XBs in an ex vivo ventricle was minimized to ∼20. Autofluorescence and photobleaching were minimized by labeling the myosin lever arm with a relatively long-lived red-emitting dye containing a chromophore system encapsulated in a cyclic macromolecule. Mutated XBs were significantly better ordered during steady-state contraction and during rigor, but the mutation had no effect on the degree of order in relaxed myofibrils. The K104E mutation increased the rate of XB binding to thin filaments and the rate of execution of the power stroke. The stopped-flow experiments revealed a significantly faster observed dissociation rate in Tg-K104E vs. Tg-wild-type (WT) myosin and a smaller second-order ATP-binding rate for the K104E compared with WT myosin. Collectively, our data indicate that the mutation-induced changes in the interaction of myosin with actin during the contraction-relaxation cycle may contribute to altered contractility and the development of FHC.

Titel:	Effect of a myosin regulatory light chain mutation K104E on actin-myosin interactions.
Autor/in / Beteiligte Person:	Duggal, D ; Nagwekar, J ; Rich, R ; Huang, W ; Midde, K ; Fudala, R ; Das, H ; Gryczynski, I ; Szczesna-Cordary, D ; Borejdo, J
Link:	Full Text Finder (Volltext)
Zeitschrift:	American journal of physiology. Heart and circulatory physiology, Jg. 308 (2015-05-15), Heft 10, S. H1248-57
Veröffentlichung:	Bethesda, Md. : American Physiological Society,, 2015
Medientyp:	academicJournal
ISSN:	1522-1539 (electronic)
DOI:	10.1152/ajpheart.00834.2014
Schlagwort:	Adenosine Triphosphate metabolism Animals Cardiomyopathy, Hypertrophic, Familial genetics Cells, Cultured Heart Ventricles cytology Heart Ventricles metabolism Mice Myofibrils metabolism Myofibrils physiology Myosin Light Chains chemistry Myosin Light Chains genetics Protein Binding Ventricular Myosins genetics Actin Cytoskeleton metabolism Cardiomyopathy, Hypertrophic, Familial metabolism Mutation, Missense Myocardial Contraction Myosin Light Chains metabolism Ventricular Myosins metabolism
Sonstiges:	Nachgewiesen in: MEDLINE Sprachen: English Publication Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Language: English [Am J Physiol Heart Circ Physiol] 2015 May 15; Vol. 308 (10), pp. H1248-57. <i>Date of Electronic Publication: </i>2015 Mar 13. MeSH Terms: Mutation, Missense* ; Myocardial Contraction* ; Actin Cytoskeleton / metabolism ; Cardiomyopathy, Hypertrophic, Familial / metabolism ; Myosin Light Chains / metabolism ; Ventricular Myosins / metabolism ; Adenosine Triphosphate / metabolism ; Animals ; Cardiomyopathy, Hypertrophic, Familial / genetics ; Cells, Cultured ; Heart Ventricles / cytology ; Heart Ventricles / metabolism ; Mice ; Myofibrils / metabolism ; Myofibrils / physiology ; Myosin Light Chains / chemistry ; Myosin Light Chains / genetics ; Protein Binding ; Ventricular Myosins / genetics References: EMBO J. 2004 Nov 24;23(23):4527-37. (PMID: 15510214) ; J Mol Cell Cardiol. 2003 Jul;35(7):841-9. (PMID: 12818575) ; J Mol Cell Cardiol. 2014 Sep;74:318-29. (PMID: 24992035) ; Science. 1993 Jul 2;261(5117):50-8. (PMID: 8316857) ; Biochemistry. 1988 Aug 9;27(16):5899-906. (PMID: 3191099) ; J Mol Biol. 2002 May 17;318(5):1275-91. (PMID: 12083517) ; Biopolymers. 1974 Jan;13(1):29-61. (PMID: 4818131) ; J Mol Biol. 2006 Aug 11;361(2):286-99. (PMID: 16837010) ; Bioconjug Chem. 1998 Mar-Apr;9(2):160-7. (PMID: 9548530) ; J Gen Physiol. 1972 Jan;59(1):103-20. (PMID: 4332133) ; Biochemistry. 1971 Dec 7;10(25):4617-24. (PMID: 4258719) ; J Med Genet. 2001 Dec;38(12):E43. (PMID: 11748309) ; J Biol Chem. 2013 Mar 8;288(10):7012-23. (PMID: 23319584) ; Biochemistry. 1984 Oct 9;23(21):4885-9. (PMID: 6238623) ; Nature. 1997 Jul 10;388(6638):186-90. (PMID: 9217160) ; Am J Physiol Heart Circ Physiol. 2006 Nov;291(5):H2098-106. (PMID: 16751284) ; FASEB J. 2009 Mar;23(3):855-65. (PMID: 18987303) ; Eur J Hum Genet. 2002 Nov;10(11):741-8. (PMID: 12404107) ; Methods Enzymol. 1998;291:307-48. (PMID: 9661157) ; Nature. 1971 Oct 22;233(5321):533-8. (PMID: 4939977) ; Biophys J. 1999 Jul;77(1):354-72. (PMID: 10388763) ; J Cardiovasc Electrophysiol. 2008 Jan;19(1):104-10. (PMID: 17916152) ; J Mol Med (Berl). 1998 Mar;76(3-4):208-14. (PMID: 9535554) ; Annu Rev Biophys Bioeng. 1975;4(00):311-34. (PMID: 1098559) ; Biophys J. 1975 May;15(5):455-67. (PMID: 19211017) ; Biophys J. 1998 Jun;74(6):3120-30. (PMID: 9635765) ; J Mol Cell Cardiol. 2010 May;48(5):989-98. (PMID: 19914255) ; Proc Natl Acad Sci U S A. 2002 Aug 6;99(16):10376-81. (PMID: 12124397) ; Biochemistry. 1994 Apr 12;33(14):4148-54. (PMID: 8155632) ; Biochemistry. 1995 Nov 14;34(45):14829-33. (PMID: 7578092) ; Adv Protein Chem. 2005;71:161-93. (PMID: 16230112) ; J Biol Chem. 2005 Nov 4;280(44):37183-94. (PMID: 16115869) ; J Mol Cell Cardiol. 2009 Jan;46(1):108-15. (PMID: 18929571) ; J Biol Chem. 2013 May 24;288(21):14780-7. (PMID: 23580644) ; Biochem J. 2012 Feb 15;442(1):95-103. (PMID: 22091967) ; Proc Natl Acad Sci U S A. 1984 Jan;81(1):145-9. (PMID: 6582471) ; J Biol Chem. 2011 Jan 7;286(1):842-50. (PMID: 21056977) ; Biophys J. 1998 Jun;74(6):3093-110. (PMID: 9635763) ; J Theor Biol. 2011 Sep 7;284(1):71-81. (PMID: 21723297) ; Proc Natl Acad Sci U S A. 1983 Dec;80(24):7515-9. (PMID: 6584869) ; Biophys J. 1996 Apr;70(4):1836-46. (PMID: 8785344) ; Biophys J. 1998 Jun;74(6):3083-92. (PMID: 9635762) ; Biophys J. 1974 Mar;14(3):236-42. (PMID: 4132695) ; Biochemistry. 2009 Feb 17;48(6):1264-71. (PMID: 19159226) ; Science. 1993 Jul 2;261(5117):58-65. (PMID: 8316858) ; J Biol Chem. 2001 Feb 9;276(6):3743-55. (PMID: 11060294) Grant Information: R01 HL071778 United States HL NHLBI NIH HHS; R01 HL123255 United States HL NHLBI NIH HHS; R01 HL108343 United States HL NHLBI NIH HHS; R01-HL-090786 United States HL NHLBI NIH HHS; R01 HL-108343 United States HL NHLBI NIH HHS; R01-AR-048622 United States AR NIAMS NIH HHS; R01 HL090786 United States HL NHLBI NIH HHS Contributed Indexing: Keywords: left ventricle; mutation of regulatory light chain; polarization of fluorescence Substance Nomenclature: 0 (Myosin Light Chains) ; 8L70Q75FXE (Adenosine Triphosphate) ; EC 3.6.1.- (Ventricular Myosins) Entry Date(s): Date Created: 20150315 Date Completed: 20150728 Latest Revision: 20200930 Update Code: 20240513 PubMed Central ID: PMC4436985

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Effect of a myosin regulatory light chain mutation K104E on actin-myosin interactions.