Myosin binding protein H (MYBPH) is a protein that in humans is encoded by the MYBPH gene. MYBPH is a structural muscle protein that shares sequence and structural similarities to myosin binding protein C (MyBPC) and is found mostly in skeletal muscle.
Gene
Aliases MYBPH is historically known as H-protein.
Location The human MYBPH gene is on the long arm of chromosome 1 (1q32.1), contains eleven exons, and spans 11,404 base pairs (bp) on the minus strand. It is immediately downstream of adenosine A1 receptor (ADORA1) and directly upstream of chitinase-3-like protein 1 (CHI3L1), as well as downstream of myogenin (MYOG) and upstream of chitinase (CHIT1).
Expression MYBPH has low to moderate expression in a number of different tissues. The gene's expression is variable and ubiquitous amongst tissues, with the highest expression, in decreasing order, in skeletal muscle, the liver, placenta, trachea, and pancreas.
Transcript variants In humans, MYBPH has two transcript variants, 1 and X1. While the main transcript variant has eleven exons, the alternative transcript variant contains an additional 5’ exon. Variant 1 is 1,818 nucleotides (nt) long and has 11 exons. Variant X1 is 3,921 nt long and contains 12 exons, differing from variant 1 in that it encodes a different N-terminus and utilizes a different promoter sequence.
Protein
Isoforms Human MYBPH's two transcript variants, 1 (477 amino acids (aa)) and X1 (518 aa), encode two protein isoforms, 1 and X1. Isoform 1 of MYBPH has a calculated molecular weight of approximately 52 kDa. Isoform X1 has a calculated molecular weight of approximately 56.4 kDa. Isoform NumberAccession NumbermRNA Length (nt)Protein Length (aa)Molecular Weight (kDa)Impact on Protein Produced1NM_004997.31,81847752Eleven exonsX1XM_047421205.13,92151856.4Twelve exons, different N-terminus encoded
Domains MYBPH has a UV excision repair protein Rad23 (Rad23) domain, two fibronectin type III (FN3) domains that also act as interdomain contacts [active] and cytokine receptor motifs [active], and two immunoglobulin (Ig and I-set) domains that each contain several Ig strands (B, C, E, F, G).
The UV excision repair protein Rad23 (Rad23) domain targets nucleotide excision repair to specific parts of the genome. Fibronectin type III (FN3) domain is an internal repeat found in fibronectin whose tenth repeat contains an Arginyl-Glycyl-Aspartic acid (RGD) cell recognition sequence. Immunoglobulin (Ig) domains are a heterogenous group of proteins built on two beta sheets.
Abundance The MYBPH protein is less abundant than most other proteins in humans, as it falls under 1 ppm. The protein's highest abundance in humans is in the skeletal muscle, following with the next highest in the esophagus.
Structure
The tertiary ribbon structure of MYBPH shows the disordered region and Rad23 domain of the strand to be a stretched out, while the fibronectin type III (FN3) domains and immunoglobulin (Ig and I-set) domains of the strand are wrapped around themselves.
Post-translational modifications
Phosphorylation and ubiquitylation There are seven predicted phosphorylation sites and four predicted ubiquitylation sites in human MYBPH, which are also present in mouse and rat MYBPH proteins.
C-mannosylation and O-GalNAc glycosylation Human MYBPH is predicted to have seven C-mannosylation sites that are not heavily conserved in strict orthologs nor distant homologs.
The protein is also predicted to have eleven O-GalNAc glycosylation sites that are not heavily conserved in strict orthologs nor distant homologs.
Homology
Orthologs
Fish are the most distantly related class to human MYBPH with the farthest median date of divergence being 429 million years ago. Whereas, mammalia is the closest related class to human MYBPH with the farthest median date of divergence being 87 million years ago. Reptilia, aves, and amphibia are moderately related to human MYBPH.
Paralogs
Human MYBPH has eight paralogs. The closest related paralog is myosin binding protein H-like (MYBPHL) and the second closest related paralog is myosin binding protein C (MyBPC).
Evolution MYBPH is estimated to have first appeared in fish approximately 429 million years ago. The protein is found in a variety of ray-finned fish and lobe-finned fish, but does not appear in cartilaginous fish. The most distantly related species compared to humans with MYBPH are lobe-finned fish. The protein is found only in vertebrates, as there are no proteins of the same identity in any invertebrates.
The gene family consists of three genes, MYBPH and its paralogs MYBPHL and MyBPC. MYBPHL appears in ray-finned fish but not lobe-finned fish, while MyBPC appears in lobe-finned fish.
MYBPH is evolving more quickly than its paralogs (MYBPHL and MyBPC), cytochrome C, and fibrinogen complement factor 1.
Function MYBPH contributes to sarcomere organization and striated muscle contraction. It is associated with the myosin filament and is active in the M band in sarcomeres. In muscle cells, MYBPH functions through binding-related activity and structural molecule activity to support the organization of the sarcomere.
Interacting proteins The protein found with the highest level of interaction with MYBPH is OCA2. Each of the proteins found to interact with MYBPH do so by either textmining, direct interaction, or physical association. Abbreviated NameFull NameBasis of IdentificationScoreConfidence ValueLinkDescriptionSourceOCA2P ProteinNot listed0.996 -TextminingInvolved in the transport of tyrosine, the precursor to melanin synthesis, within the melanocyte.STRINGGLDCGlycine DehydrogenaseNot listed0.994 -TextminingCatalyzes the degradation of glycine.STRINGSLAMF1Signaling Lymphocytic Activation MoleculeNot listed0.994 -TextminingSelf-ligand receptor of the signaling lymphocytic activation molecule (SLAM) family.STRINGCD46Membrane Cofactor ProteinNot listed0.993 -TextminingActs as a cofactor for complement factor I.STRINGNECTIN4Processed Poliovirus Receptor-Related Protein 4Not listed0.993 -TextminingInvolved in cell adhesion through trans-homophilic and -heterophilic interactions.STRINGAMTAminomethyltransferaseNot listed0.984 -TextminingCatalyzes the degradation of glycine.STRINGGCSHGlycine Cleavage System H ProteinNot listed0.957 -TextminingCatalyzes the degradation of glycine.STRINGC3Complement C3c Alpha Chain Fragment 1Not listed0.857 -TextminingPlays a role in the activation of the complement system.STRINGTLR2Toll-Like Receptor 2Not listed0.836 -TextminingWorks with LY96 to mediate the innate immune response to bacterial lipoproteins and other microbial cell wall components.STRINGCFHComplement Factor HNot listed0.798 -TextminingGlycoprotein that plays a role in maintaining a well-balanced immune response by modulating complement activation.STRINGROCK1Rho-Associated Coiled-Coil Containing Protein Kinase 1Pull down -0.54Direct interactionRegulates the shape, movement, and structural foundation of cells.MINT - PSICQUICBAG3Bcl2 Associated Athanogene 3Affinity chromatography -465Physical associationRegulates apoptosis, development, cell motility, autophagy, and tumor metastasis and mediates cell adaptive responses to stressful stimuli.InnateDB - PSICQUICUBL7Ubiquitin-Like Protein SB132Two hybrid fragment pooling -0.37Physical associationRegulator of protein homeostasis and innate immunity.IMEx - PSICQUICCAPN3Calcium-Activated Neutral Proteinase 3Two hybrid fragment pooling -0.37Physical associationBreaks down damaged proteins for removal, organizes muscle units, and regulates calcium levels essential for muscle contraction and relaxation.IMEx - PSICQUIC
Clinical significance MYBPH was discovered in acting as a modifier of cardiac hypertrophy in hypertrophic cardiomyopathy (HCM) patients. It is shown to function in concert with cardiac myosin binding protein C (cMYBPC) in regulating cardiomyocyte contraction. There is a significant association between a MYBPH variant (rs2250509) and hypertrophy traits in one of the HCM-causing founder mutations (pA797T in β-myosin heavy chain gene (MYH7)).
MYBPH is a transcriptional target of Thyroid Transcription Factor-1 (TTF-1) that inhibits assembly competence-conferring phosphorylation of the myosin regulatory light chain (RLC) and activates phosphorylation of LIM domain kinase (LIMK) through its interaction with Rho kinase 1 (ROCK1). MYBPH's interaction with ROCK1 inhibits the enzyme and negatively regulates actomyosin organization, reducing single cell motility and increasing collective cell migration that results in decreased cancer invasion and metastasis.
References