title: Loss of actomyosin regulation in distal arthrogryposis myopathy due to mutant myosin binding protein-C slow.
abstract: Myosin binding protein C (MyBP-C) is expressed in striated muscles, where it plays key roles in the modulation of actomyosin cross-bridges. Slow MyBP-C (sMyBP-C) consists of multiple variants sharing common domains but also containing unique segments within the NH2 and COOH termini. Two missense mutations in the NH2 terminus (W236R) and COOH terminus (Y856H) of sMyBP-C have been causally linked to the development of distal arthrogryposis-1 (DA-1), a severe skeletal muscle disorder. Using a combination of in vitro binding and motility assays, we show that the COOH terminus mediates binding of sMyBP-C to thick filaments, while the NH2 terminus modulates the formation of actomyosin cross-bridges in a variant-specific manner. Consistent with this, a recombinant NH2-terminal peptide that excludes residues 34-59 reduces the sliding velocity of actin filaments past myosin heads from 9.0 ± 1.3 to 5.7 ± 1.0 μm/s at 0.1 μM, while a recombinant peptide that excludes residues 21-59 fails to do so. Notably, the actomyosin regulatory properties of sMyBP-C are completely abolished by the presence of the DA-1 mutations. In summary, our studies are the first to show that the NH2 and COOH termini of sMyBP-C have distinct functions, which are regulated by differential splicing, and are compromized by the presence of missense point mutations linked to muscle disease.
authors: Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, 108 N. Greene St, Baltimore, MD 21201, USA.
authors: Maegen A
authors: MA
authors: Ackermann
authors: Puja D
authors: PD
authors: Patel
authors: Jane
authors: J
authors: Valenti
authors: Yasuharu
authors: Y
authors: Takagi
authors: Earl
authors: E
authors: Homsher
authors: James R
authors: JR
authors: Sellers
authors: Aikaterini
authors: A
authors: Kontrogianni-Konstantopoulos
mesh_terms: D000199:Actins / Q000737:chemistry / Q000378:metabolism; D000205:Actomyosin / Q000737:chemistry / Q000378:metabolism*; D017398:Alternative Splicing; D019943:Amino Acid Substitution; D000818:Animals; D001176:Arthrogryposis / Q000235:genetics / Q000378:metabolism*; D001665:Binding Sites / Q000235:genetics; D026481:Blotting, Far-Western; D002352:Carrier Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D049310:Distal Myopathies / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008954:Models, Biological; D008958:Models, Molecular; D018482:Muscle, Skeletal / Q000378:metabolism; D009154:Mutation; D009218:Myosins / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D000099163:Myosin Binding Protein C
chemical_list: D000199:Actins; D000205:Actomyosin; D002352:Carrier Proteins; D009218:Myosins; D000099163:Myosin Binding Protein C
keywords: MYBPC1; actin; contractility; skeletal muscle
references: Methods Enzymol. 1991;196:399-416
references: 2034132
references: J Biol Chem. 2009 May 1;284(18):12318-27
references: 19269976
references: Hum Mol Genet. 2010 Apr 1;19(7):1165-73
references: 20045868
references: Circ Res. 2011 Mar 18;108(6):751-64
references: 21415409
references: Circ Res. 2006 May 26;98(10):1234-6
references: 16728667
references: Mol Biol Cell. 2009 Jun;20(12):2963-78
references: 19403693
references: J Biol Chem. 2011 Jan 21;286(3):2008-16
references: 21071444
references: Adv Exp Med Biol. 1993;332:279-89; discussion 289-90
references: 8109342
references: Curr Protoc Cell Biol. 2001 May;Chapter 13:Unit 13.2
references: 18228321
references: J Cell Biol. 1993 Nov;123(3):619-26
references: 8227129
references: Int J Biochem Cell Biol. 2007;39(12):2161-6
references: 17320463
references: J Mol Cell Cardiol. 2004 Oct;37(4):823-35
references: 15380673
references: J Mol Cell Cardiol. 1995 Oct;27(10):2275-86
references: 8576942
references: J Cell Sci Suppl. 1991;14:67-71
references: 1885662
references: J Mol Cell Cardiol. 2004 Oct;37(4):813-5
references: 15380671
references: J Cell Sci. 1996 Jan;109 ( Pt 1):101-11
references: 8834795
references: Proc Natl Acad Sci U S A. 1990 Mar;87(6):2157-61
references: 2315308
references: Biochemistry. 2000 May 9;39(18):5555-60
references: 10820029
references: J Biol Chem. 1971 Aug 10;246(15):4866-71
references: 4254541
references: J Biol Chem. 2011 Apr 8;286(14):12650-8
references: 21297165
references: J Mol Biol. 2003 Aug 15;331(3):713-24
references: 12899839
references: J Biomed Biotechnol. 2011;2011:636403
references: 22028592
references: Eur J Biochem. 1993 Sep 1;216(2):661-9
references: 8375400
references: J Biol Chem. 2007 Mar 23;282(12):9204-15
references: 17192269
references: J Biol Chem. 2011 Mar 25;286(12):9913-9
references: 21257752
references: J Mol Biol. 1999 Feb 26;286(3):933-49
references: 10024460
references: Biochem J. 2007 Jan 1;401(1):97-102
references: 16918501
references: J Mol Biol. 1978 Oct 5;124(4):571-86
references: 152359
references: J Struct Biol. 2011 Apr;174(1):44-51
references: 21163356
references: J Mol Biol. 1975 Sep 5;97(1):1-9
references: 1100851
references: J Cell Sci. 2002 Sep 1;115(Pt 17):3517-26
references: 12154082
references: Circ Res. 1998 Jan 9-23;82(1):124-9
references: 9440711
references: Methods Enzymol. 1982;85 Pt B:55-71
references: 6214692
references: J Proteome Res. 2011 Oct 7;10(10):4547-55
references: 21888435
references: Hum Mutat. 2012 Oct;33(10):1435-8
references: 22610851
references: J Biol Chem. 2007 Nov 2;282(44):32384-96
references: 17720975
references: J Biol Chem. 1997 Aug 15;272(33):20866-72
references: 9252413
references: J Biomed Biotechnol. 2010;2010:652065
references: 20396395
references: J Biol Chem. 2009 Apr 24;284(17):11563-71
references: 19240025
references: J Muscle Res Cell Motil. 2012 May;33(1):61-74
references: 22415774