Myosin Binding Protein C, Cardiac

Myosin binding protein C, cardiac
The myosin-binding protein C,

MYBPC3
cardiac-type is a protein that in
humans is encoded by the
MYBPC3 gene.[5] This isoform is
expressed exclusively in heart
muscle during human and mouse
development,[6] and is distinct
from those expressed in slow
skeletal muscle (MYBPC1) and
fast skeletal muscle (MYBPC2).
Available structures
PDB Ortholog search: PDBe (https://www.ebi.ac.uk/pdbe/search
Contents Results.html?display=both&term=O70468%20or%20Q1489
Structure 6%20or%20A5YM48) RCSB (http://www.rcsb.org/pdb/searc
Function h/smartSubquery.do?smartSearchSubtype=UpAccessionId
Query&accessionIdList=O70468,Q14896,A5YM48)
Genetics
List of PDB id codes
Pathomechanisms
Therapy 1GXE (https://www.rcsb.org/structure/1GXE), 2AVG
(https://www.rcsb.org/structure/2AVG), 2K1M (http
Notes
s://www.rcsb.org/structure/2K1M), 2MQ0 (https://w
References ww.rcsb.org/structure/2MQ0), 2MQ3 (https://www.rc
Further reading sb.org/structure/2MQ3), 2V6H (https://www.rcsb.or
External links g/structure/2V6H), 3CX2 (https://www.rcsb.org/stru
cture/3CX2), 1PD6 (https://www.rcsb.org/structure/
1PD6)
Structure
Identifiers
cMyBP-C is a 140.5 kDa protein
composed of 1273 amino Aliases MYBPC3 (https://www.genenames.org/cgi-bin/gene_symb
acids.[7][8][9] cMyBP-C is a ol_report?hgnc_id=7551), CMD1MM, CMH4, FHC,
myosin-associated protein that LVNC10, MYBP-C, Myosin binding protein C, cardiac,
binds at 43 nm intervals along the cMyBP-C, myosin binding protein C3
myosin thick filament backbone, External OMIM: 600958 (https://omim.org/entry/600958) MGI:
stretching for 200 nm on either IDs 102844 (http://www.informatics.jax.org/marker/MGI:10284
side of the M-line within the 4) HomoloGene: 215 (https://www.ncbi.nlm.nih.gov/entre
crossbridge-bearing zone (C- z/query.fcgi?cmd=Retrieve&db=homologene&dopt=Homol
region) of the A band in striated oGene&list_uids=215) GeneCards: MYBPC3 (https://ww
muscle.[10] The approximate w.genecards.org/cgi-bin/carddisp.pl?gene=MYBPC3)
stoichiometry of cMyBP-C along Gene location (Human)
the thick filament is 1 per 9-10
myosin molecules, or 37 cMyBP-
C molecules per thick
filament.[11] In addition to
myosin, cMyBP-C also binds titin
and actin.[12][13] The cMyBP-C
isoform expressed in cardiac
muscle differs from those
expressed in slow and fast skeletal Chr. Chromosome 11 (human)[1]
muscle (MYBPC1 and MYBPC2,
respectively) by three features: (1)
an additional immunoglobulin
(Ig)-like domain on the N- Band 11p11.2 Start 47,331,406 bp[1]
terminus, (2) a linker region End 47,352,702 bp[1]
between the second and third Ig
domains, and (3) an additional Gene location (Mouse)
loop in the sixth Ig domain.[14]
cMyBP-C appears necessary for
normal order, filament length and
lattice spacing within the structure
of the sarcomere.[15][16]
Chr. Chromosome 2 (mouse)[2]
Function
cMyBP-C is not essential for
sarcomere formation during
embryogenesis, but is crucial for Band 2|2 E1 Start 91,118,144 bp[2]
sarcomere organization and End 91,136,516 bp[2]
maintenance of normal cardiac RNA expression pattern
function. Absence of cMyBP-C
(Mybpc3-targeted knock-out
mice) results in severe cardiac
hypertrophy, increased heart-
weight-to-body-weight-ratios,
enlargement of ventricles,
increased myofilament Ca2+
sensitivity and depressed diastolic
and systolic function.[17][18][19]
Histologically, Mybpc3-targeted More reference expression data (http://biogps.org/gene/4607/)
knock-out hearts display
structural rearrangements with Gene ontology
cardiac myocyte disarray and Molecular • myosin binding (http://amigo.geneontology.org/amigo/
increased interstitial fibrosis function term/GO:0017022)
similar to patients with • titin binding (http://amigo.geneontology.org/amigo/ter
hypertrophic cardiomyopathy, m/GO:0031432)
without obvious alterations in • metal ion binding (http://amigo.geneontology.org/ami
shape or size of single cardiac go/term/GO:0046872)
myocytes. Ultrastructural • myosin heavy chain binding (http://amigo.geneontolo
examination revealed a loss of gy.org/amigo/term/GO:0032036)
lateral alignment of adjacent • GO:0001948 protein binding (http://amigo.geneontolo
myofibrils with their Z-lines gy.org/amigo/term/GO:0005515,)
misaligned.[17][18][20][21] • identical protein binding (http://amigo.geneontology.or
g/amigo/term/GO:0042802)
cMyBP-C appears to act as a • actin binding (http://amigo.geneontology.org/amigo/te
brake on cardiac contraction, as rm/GO:0003779)
loaded shortening, power and
• ATPase activator activity (http://amigo.geneontology.
cycling kinetics all increase in
org/amigo/term/GO:0001671)
cMyBP-C knockout mice.[22]
• structural constituent of muscle (http://amigo.geneont
Consistent with this notion,
ology.org/amigo/term/GO:0008307)
cMyBP-C knockout mice exhibit
• actin filament binding (http://amigo.geneontology.org/
an abnormal systolic timecourse,
amigo/term/GO:0051015)
with a shortened elastance
• muscle alpha-actinin binding (http://amigo.geneontolo
timecourse and lower peak
gy.org/amigo/term/GO:0051371)
elastance in vivo,[23] and an
• structural molecule activity conferring elasticity (http://
accelerated force development in
amigo.geneontology.org/amigo/term/GO:0097493)
isolated, skinned cardiac fibers[24]
suggesting that cMyBP-C is Cellular • cytosol (http://amigo.geneontology.org/amigo/term/G
required to constrain the component O:0005829)
crossbridges in order to sustain a • C zone (http://amigo.geneontology.org/amigo/term/G
normal ejection. O:0014705)
• sarcomere (http://amigo.geneontology.org/amigo/ter
cMyBP-C regulates the m/GO:0030017)
positioning of myosin and actin • striated muscle myosin thick filament (http://amigo.ge
for interaction and acts as a tether neontology.org/amigo/term/GO:0005863)
to the myosin S1 heads, limiting • myosin filament (http://amigo.geneontology.org/amig
their mobility. This results in a o/term/GO:0032982)
decreased number of crossbridges • A band (http://amigo.geneontology.org/amigo/term/G
formed, which hinders force O:0031672)
generation, due to its N-terminal • Z disc (http://amigo.geneontology.org/amigo/term/G
C1-M-C2 region interacting with O:0030018)
the myosin-S2 • M band (http://amigo.geneontology.org/amigo/term/G
domain. [25][26][27][28]
O:0031430)
Furthermore, cMyBP-C
• cardiac myofibril (http://amigo.geneontology.org/amig
contributes to the regulation of
o/term/GO:0097512)
cardiac contraction at short
• striated muscle thin filament (http://amigo.geneontolo
sarcomere length and is required
gy.org/amigo/term/GO:0005865)
for complete relaxation in
diastole.[19][29] Biological • regulation of muscle filament sliding (http://amigo.gen
process eontology.org/amigo/term/GO:0032971)
Interactions of cMyBP-C with its • positive regulation of ATPase activity (http://amigo.ge
binding partners vary with its neontology.org/amigo/term/GO:0032781)
posttranslational modification • cardiac muscle contraction (http://amigo.geneontolog
status. At least three extensively y.org/amigo/term/GO:0060048)
characterized phosphorylation • heart morphogenesis (http://amigo.geneontology.org/
sites (Ser273, 282 and 302; amigo/term/GO:0003007)
numbering refers to the mouse • ventricular cardiac muscle tissue morphogenesis (htt
sequence) are localized in the M p://amigo.geneontology.org/amigo/term/GO:0055010)
motif of cMyBP-C and are • regulation of striated muscle contraction (http://amig
targeted by protein kinases in a o.geneontology.org/amigo/term/GO:0006942)
hierarchical order of events. In its • cell adhesion (http://amigo.geneontology.org/amigo/te
dephosphorylated state, cMyBP-C rm/GO:0007155)
binds predominantly to myosin S2 • muscle filament sliding (http://amigo.geneontology.or
and brakes crossbridge formation, g/amigo/term/GO:0030049)
however, when phosphorylated in • striated muscle contraction (http://amigo.geneontolog
response to β-adrenergic y.org/amigo/term/GO:0006941)
stimulation through activating • actin filament organization (http://amigo.geneontolog
cAMP-dependent protein kinase y.org/amigo/term/GO:0007015)
(PKA), it favours binding to actin, • sarcomere organization (http://amigo.geneontology.or
then accelerating crossbridge g/amigo/term/GO:0045214)
formation, enhancing force • striated muscle myosin thick filament assembly (htt
development and promoting p://amigo.geneontology.org/amigo/term/GO:0071688)
relaxation. [30] Protein kinases • muscle contraction (http://amigo.geneontology.org/a
identified thus far to migo/term/GO:0006936)
phosphorylate cMyBP-C in the M
• skeletal muscle thin filament assembly (http://amigo.g
motif are PKA,[31][32][33][34][35] eneontology.org/amigo/term/GO:0030240)
Ca2+/calmodulin-dependent
• skeletal muscle myosin thick filament assembly (htt
kinase II (CaMKII),[36] ribosomal
p://amigo.geneontology.org/amigo/term/GO:0030241)
s6 kinase (RSK),[37]protein kinase
• cardiac muscle fiber development (http://amigo.gene
D (PKD),[38][39] and protein
ontology.org/amigo/term/GO:0048739)
kinase C (PKC).[34] Furthermore,
• cardiac myofibril assembly (http://amigo.geneontolog
GSK3β was described as another
y.org/amigo/term/GO:0055003)
protein kinase to phosphorylate
• cardiac muscle tissue morphogenesis (http://amigo.g
cMyBP-C outside the M-domain
eneontology.org/amigo/term/GO:0055008)
in the proline-alanine-rich actin-
binding site at Ser133 in human Sources:Amigo (http://amigo.geneontology.org/) / QuickGO (https://
myocardium (mouse Ser131).[40] www.ebi.ac.uk/QuickGO/)
Phosphorylation is required for Orthologs
normal cardiac function and
Species Human Mouse
cMyBP-C stability,[41][42] and
Entrez
overall phosphorylation levels of 4607 (https://www.ncb 17868 (https://www.ncbi.
cMyBP-C are reduced in human i.nlm.nih.gov/entrez/q nlm.nih.gov/entrez/query.
and experimental heart uery.fcgi?db=gene&c fcgi?db=gene&cmd=retri
failure. [43][44] Other md=retrieve&dopt=def eve&dopt=default&list_ui
posttranslational modifications of ault&list_uids=4607&r ds=17868&rn=1)
cMyBP-C exist, which occur n=1)
throughout the protein and are not
thoroughly characterised yet, such Ensembl
as acetylation,[45] ENSG00000134571 ENSMUSG00000002100
citrullination,[46] S- (http://www.ensembl.o (http://www.ensembl.org/
glutathiolation, [47][48][49][50] S- rg/Homo_sapiens/gen Mus_musculus/genevie
nitrosylation [51] and eview?gene=ENSG00 w?gene=ENSMUSG000
carbonylation. [52] 000134571;db=core) 00002100;db=core)
Genetics UniProt
The cloning of the human Q14896 (https://www. O70468 (https://www.uni
MYBPC3 cDNA and localization uniprot.org/uniprot/Q1 prot.org/uniprot/O70468)
of the gene on human 4896)
chromosome 11p11.2 has assisted
the structure and function of RefSeq
cMyBP-C.[53] MYBPC3 became (mRNA)
NM_000256 (https://w NM_008653 (https://ww
therefore the “best” candidate ww.ncbi.nlm.nih.gov/e w.ncbi.nlm.nih.gov/entre
gene for the CMH4 locus for ntrez/viewer.fcgi?val= z/viewer.fcgi?val=NM_00
hypertrophic cardiomyopathy that NM_000256) 8653)
was initially mapped by the group
of Schwartz.[54] MYBPC3 RefSeq
NP_000247 (https://w n/a
mutations segregating in families (protein)
ww.ncbi.nlm.nih.gov/e
with hypertrophic
ntrez/viewer.fcgi?val=
cardiomyopathy have been
[55][56] NP_000247)
identified. MYBPC3 was
NP_000247.2 (https://
thus the fourth gene for
www.ncbi.nlm.nih.gov/
hypertrophic cardiomyopathy,
entrez/viewer.fcgi?val
following MYH7, encoding β-
=NP_000247.2)
myosin heavy chain, TNNT2 and
TPM1, encoding cardiac troponin
Location Chr 11: 47.33 – 47.35 Mb Chr 2: 91.12 – 91.14 Mb (http
T and α-tropomyosin,
(UCSC) (https://genome.ucsc.edu/ s://genome.ucsc.edu/cgi-bin/
respectively, earmarking
cgi-bin/hgTracks?org=Hu hgTracks?org=Mouse&db=m
hypertrophic cardiomyopathy as a
man&db=hg38&position=c m0&position=chr2:91118144-
disease of the sarcomere.
hr11:47331406-47352702) 91136516)
To date, roughly 350 mutations in PubMed [3] [4]
MYBPC3 have been identified, search

and in large part, the mutations Wikidata
result in protein truncation, shifts
View/Edit Human View/Edit Mouse
in reading frames, and premature
termination codons.[57][58]
Genetic studies have revealed significant overlap between genotypes and phenotypes as MYBPC3
mutations can lead to various forms of cardiomyopathies, such as dilated cardiomyopathy[59] and left
ventricular noncompaction cardiomyopathy.[60] In patients with isolated or familial cases of dilated
cardiomyoathy, MYBPC3 mutations represented the second highest number of known mutations.[59]
Furthermore, a 25-bp intronic MYBPC3 deletion leading to protein truncation is present in 4% of the
population in South India and is associated with a higher risk to develop heart failure.[61] Founder
MYBPC3 mutations have been reported in Iceland, Italy, The Netherlands, Japan, France and Finland,
where they represent a large percentage of cases with hypertrophic cardiomyopathy. All of them are
truncating mutations, resulting in a shorter protein, lacking the regulatory phosphorylatable M motif
and/or major binding domains to other sarcomeric proteins.[62][63][64][65][66][67][68] A body of evidence
indicates that patients with more than 1 mutation often develop a more severe phenotype,[69] and a
significant fraction of childhood-onset hypertrophic cardiomyopathy(14%) is caused by compound
genetic variants.[70] This suggests that a gene-dosage effect might be responsible for manifestations at a
younger age. A total of 51 cases of homozygotes or compound heterozygotes have been reported, most of
them with double truncating MYBPC3 mutations and associated with severe cardiomyopathy, leading to
heart failure and death within the first year of life.[71]
Pathomechanisms
A great understanding of how MYBPC3 mutations lead to the development of inherited cardiomyopathy
came from the analyses of human myocardial samples, gene transfer in different cell lines, naturally-
occurring or transgenic animal models and more recently disease modeling using induced pluripotent
stem cells (iPSC)-derived cardiac myocytes.[72][73] Although access to human myocardial samples is
difficult, at least some studies provided evidence that truncated cMyBP-Cs, resulting from truncating
MYBPC3 mutations are not detectable in human patient samples by Western-immunoblot
analysis.[74][75][76][77] This was supported in heterozygous Mybpc3-targeted knock-in mice,[78] carrying
the human c.772G>A transition (i.e. founder mutation in Tuscany[66] These data suggest
haploinsufficiency as the main disease mechanism for heterozygous truncating mutations.[79][80] A body
of evidence exists that the mechanisms regulating the expression of mutant allele involve the nonsense-
mediated mRNA decay, the ubiquitin-proteasome system (UPS) and the autophagy-lysosomal pathway
after gene transfer of mutant MYBPC3 in cardiac myocytes or in mice in vivo.[81][82][83][84][85][86] In
contrast to truncating mutations, missense mutations lead, in most of the cases (although difficult to
specifically detect), to stable mutant cMyBP-Cs that are, at least in part, incorporated into the sarcomere
and could act as poison polypeptides on the structure and/or function of the sarcomere. Homozygous or
compound heterozygous mutations are therefore likely subject to differential regulation depending on
whether they are double missense, double truncating or mixed missense/truncating mutations. The
homozygous Mybpc3-targeted knock-in mice, which genetically mimic the situation of severe neonatal
cardiomyopathy are born without phenotype and soon after birth develop systolic dysfunction followed
by (compensatory) cardiac hypertrophy.[87][88] The human c.772G>A transition results in low levels of
three different mutant Mybpc3 mRNAs and cMyBP-Cs in homozygous mice, suggesting a combination
of haploinsufficiency and polypeptide poisoning as disease mechanism in the homozygous state.[89] In
addition, the combination of external stress (such as neurohumoral stress or aging) and Mybpc3
mutations have been shown to impair the UPS in mice,[90][91] and proteasomal activities were also
depressed in patients with hypertrophic cardiomyopathy or dilated cardiomyopathy.[92]
Skinned trabeculae or cardiac myocytes obtained from human patients carrying a MYBPC3 mutation or
from heterozygous and homozygous Mybpc3-targeted knock-in mice exhibited higher myofilament Ca2+
sensitivity than controls.[93][94][95][96][97] Disease-modeling by engineered heart tissue (EHT)
technology with cardiac cells from heterozygous or homozygous Mybpc3-targeted knock-in mice
reproduced observations made in human and mouse studies displaying abbreviated contractions, greater
sensitivity to external Ca2+ and smaller inotropic responses to various drugs (isoprenaline, EMD 57033
and verapamil) compared to wild-type control EHTs.[98] Therefore, EHTs are suitable to model the
disease phenotype and recapitulate functional alterations found in mice with hypertrophic
cardiomyopathy. Another good system for modeling cardiomyopathies in the cell culture dish is the
derivation of cardiac myocytes from iPSC. Reports of human iPSC models of sarcomeric
cardiomyopathies showed cellular hypertrophy in most of the cases,[99][100][101][102] including one with
the c.2995_3010del MYBPC3 mutation that exhibited in addition to hypertrophy contractile variability in
the presence of endothelin-1.[103]
Therapy
Because of their tissue selectivity and persistent expression recombinant adeno-associated viruses (AAV)
have therapeutic potential in the treatment of inherited cardiomyopathy resulting from MYBPC3
mutations-[104] Several targeting approaches have been developed.[105][106] The most recent is genome
editing to correct a mutation by CRISPR/Cas9 technology.[107] Naturally existing as part of the
prokaryotic immune system, the CRISPR/Cas9 system has been used for correction of mutations in the
mammalian genome.[108] By inducing nicks in the double-stranded DNA and providing a template DNA
sequence, it is possible to repair mutations by homologous recombination. This approach has not yet
been evaluated for MYBPC3 mutations, but it could be used for each single or clustered mutation, and
therefore applied preferentially for frequent founder MYBPC3 mutations.
Other strategies targeting the mutant pre-mRNA by exon skipping and/or spliceosome-mediated RNA
trans-splicing (SMaRT) have been evaluated for MYBPC3. Exon skipping can be achieved using
antisense oligonucleotide (AON) masking exonic splicing enhancer sequences and therefore preventing
binding of the splicing machinery and therefore resulting in exclusion of the exon from the
mRNA.[109][110] This approach can be applied when the resulting shorter, but in-frame translated protein
maintains its function. Proof-of-concept of exon skipping was recently shown in homozygous Mybpc3-
targeted knock-in mice.[87] Systemic administration of AAV-based AONs to Mybpc3-targeted knock-in
newborn mice prevented both systolic dysfunction and left ventricular hypertrophy, at least for the
duration of the investigated period.[87] For the human MYBPC3 gene, skipping of 6 single exons or 5
double exons with specific AONs would result in shortened in-frame cMyBP-Cs, allowing the
preservation of the functionally important phosphorylation and protein interaction sites. With this
approach, about half of missense or exonic/intronic truncating mutations could be removed, including 35
mutations in exon 25. The other strategy targeting the mutant pre-mRNA is SMaRT. Hereby, two
independently transcribed molecules, the mutant pre-mRNA and the therapeutic pre-trans-splicing
molecule carrying the wild-type sequence are spliced together to give rise to a repaired full-length
mRNA.[111] Recently, the feasibility of this method was shown both in isolated cardiac myocytes and in
vivo in the heart of homozygous Mybpc3-targeted knock-in mice, although the efficiency of the process
was low and the amount of repaired protein was not sufficient to prevent the development of the cardiac
disease phenotype.[88] In principle, however, this SmART strategy is superior to exon skipping or
CRISPR/Cas9 genome editing and still attractive, because only two pre-trans-splicing molecules,
targeting the 5’ and the 3’ of MYBPC3 pre-mRNA would be sufficient to bypass all MYBPC3 mutations
associated with cardiomyopathies and therefore repair the mRNA.
AAV-mediated gene transfer of the full-length Mybpc3 (defined as “gene replacement”) dose-
dependently prevents the development of cardiac hypertrophy and dysfunction in homozygous Mybpc3-
targeted knock-in mice.[112] The dose-dependent expression of exogenous Mybpc3 was associated with
the down-regulation of endogenous mutant Mybpc3. Additional expression of a sarcomeric protein is
expected to replace partially or completely the endogenous protein level in the sarcomere, as it has been
shown in transgenic mice expressing sarcomeric proteins.[113]
Notes
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External links
Mass spectrometry characterization of MYBPC3 at COPaKB (http://www.heartproteome.or
g/copa/ProteinInfo.aspx?QType=Protein%20ID&QValue=Q14896)
GeneReviews/NIH/NCBI/UW entry on Familial Hypertrophic Cardiomyopathy Overview (http
s://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=hyper-card)
Overview of all the structural information available in the PDB for UniProt: Q14896 (https://w
ww.ebi.ac.uk/pdbe/pdbe-kb/proteins/Q14896) (Myosin-binding protein C, cardiac-type) at
the PDBe-KB.
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