Document Detail


Determination of the critical residues responsible for cardiac myosin binding protein C's interactions.
MedLine Citation:
PMID:  22982234     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Despite early demonstrations of myosin binding protein C's (MyBP-C) interaction with actin, different investigators have reached different conclusions regarding the relevant and necessary domains mediating this binding. Establishing the detailed structure-function relationships is needed to fully understand cMyBP-C's ability to impact on myofilament contraction as mutations in different domains are causative for familial hypertrophic cardiomyopathy. We defined cMyBP-C's N-terminal structural domains that are necessary or sufficient to mediate interactions with actin and/or the head region of the myosin heavy chain (S2-MyHC). Using a combination of genetics and functional assays, we defined the actin binding site(s) present in cMyBP-C. We confirmed that cMyBP-C's C1 and m domains productively interact with actin, while S2-MyHC interactions are restricted to the m domain. Using residue-specific mutagenesis, we identified the critical actin binding residues and distinguished them from the residues that were critical for S2-MyHC binding. To validate the structural and functional significance of these residues, we silenced the endogenous cMyBP-C in neonatal rat cardiomyocytes (NRC) using cMyBP-C siRNA, and replaced the endogenous cMyBP-C with normal or actin binding-ablated cMyBP-C. Replacement with actin binding-ablated cMyBP-C showed that the mutated protein did not incorporate into the sarcomere normally. Residues responsible for actin and S2-MyHC binding are partially present in overlapping domains but are unique. Expression of an actin binding-deficient cMyBP-C resulted in abnormal cytosolic distribution of the protein, indicating that interaction with actin is essential for the formation and/or maintenance of normal cMyBP-C sarcomeric distribution.
Authors:
Md Shenuarin Bhuiyan; James Gulick; Hanna Osinska; Manish Gupta; Jeffrey Robbins
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2012-09-11
Journal Detail:
Title:  Journal of molecular and cellular cardiology     Volume:  53     ISSN:  1095-8584     ISO Abbreviation:  J. Mol. Cell. Cardiol.     Publication Date:  2012 Dec 
Date Detail:
Created Date:  2012-11-12     Completed Date:  2013-04-19     Revised Date:  2013-12-04    
Medline Journal Info:
Nlm Unique ID:  0262322     Medline TA:  J Mol Cell Cardiol     Country:  England    
Other Details:
Languages:  eng     Pagination:  838-47     Citation Subset:  IM    
Copyright Information:
Copyright © 2012 Elsevier Ltd. All rights reserved.
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MeSH Terms
Descriptor/Qualifier:
Actins / chemistry,  metabolism
Amino Acid Sequence
Animals
Binding Sites
Carrier Proteins / chemistry*,  genetics,  metabolism*
Gene Silencing
Mice
Molecular Sequence Data
Myocytes, Cardiac / metabolism*
Myosin Subfragments / chemistry,  metabolism
Protein Binding / genetics
Protein Interaction Domains and Motifs
RNA Interference
Rats
Sequence Alignment
Grant Support
ID/Acronym/Agency:
P01 HL059408/HL/NHLBI NIH HHS; P01 HL069779/HL/NHLBI NIH HHS; P01HL059408/HL/NHLBI NIH HHS; P01HL69779/HL/NHLBI NIH HHS; R01 HL068552/HL/NHLBI NIH HHS; R011062927//PHS HHS; R01HL05924/HL/NHLBI NIH HHS; S10 RR027014/RR/NCRR NIH HHS
Chemical
Reg. No./Substance:
0/Actins; 0/Carrier Proteins; 0/Myosin Subfragments; 0/myosin-binding protein C
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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