UniProt functional annotation for Q8WZ42



	UniProt functional annotation for Q8WZ42

UniProt code: Q8WZ42.

Organism: Homo sapiens (Human).

Taxonomy: Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.

Function: Key component in the assembly and functioning of vertebrate striated muscles. By providing connections at the level of individual microfilaments, it contributes to the fine balance of forces between the two halves of the sarcomere. The size and extensibility of the cross-links are the main determinants of sarcomere extensibility properties of muscle. In non-muscle cells, seems to play a role in chromosome condensation and chromosome segregation during mitosis. Might link the lamina network to chromatin or nuclear actin, or both during interphase. {ECO:0000269|PubMed:9804419}.

Catalytic activity: Reaction=ATP + L-seryl-[protein] = ADP + H(+) + O-phospho-L-seryl- [protein]; Xref=Rhea:RHEA:17989, Rhea:RHEA-COMP:9863, Rhea:RHEA- COMP:11604, ChEBI:CHEBI:15378, ChEBI:CHEBI:29999, ChEBI:CHEBI:30616, ChEBI:CHEBI:83421, ChEBI:CHEBI:456216; EC=2.7.11.1;

Catalytic activity: Reaction=ATP + L-threonyl-[protein] = ADP + H(+) + O-phospho-L- threonyl-[protein]; Xref=Rhea:RHEA:46608, Rhea:RHEA-COMP:11060, Rhea:RHEA-COMP:11605, ChEBI:CHEBI:15378, ChEBI:CHEBI:30013, ChEBI:CHEBI:30616, ChEBI:CHEBI:61977, ChEBI:CHEBI:456216; EC=2.7.11.1;

Cofactor: Name=Mg(2+); Xref=ChEBI:CHEBI:18420;

Activity regulation: Full activation of the protein kinase domain requires both phosphorylation of Tyr-32341, preventing it from blocking the catalytic aspartate residue, and binding of Ca/CALM to the C- terminal regulatory tail of the molecule which results in ATP binding to the kinase. {ECO:0000269|PubMed:9804419}.

Subunit: Interacts with MYOM1, MYOM2, tropomyosin and myosin. Interacts with actin, primarily via the PEVK domains and with MYPN (By similarity). Interacts with FHL2, NEB, CRYAB, LMNA/lamin-A and LMNB/lamin-B. Interacts with TCAP/telethonin and/or ANK1 isoform Mu17/ank1.5, via the first two N-terminal immunoglobulin domains. Interacts with TRIM63 and TRIM55, through several domains including immunoglobulin domains 141 and 142. Interacts with ANKRD1, ANKRD2 and ANKRD23, via the region between immunoglobulin domains 77 and 78 and interacts with CAPN3, via immunoglobulin domain 79. Interacts with NBR1 through the protein kinase domain. Interacts with CALM/calmodulin. Isoform 6 interacts with OBSCN isoform 3. Interacts with CMYA5. {ECO:0000250, ECO:0000269|PubMed:11717165, ECO:0000269|PubMed:12432079, ECO:0000269|PubMed:12444090, ECO:0000269|PubMed:12482578, ECO:0000269|PubMed:14583192, ECO:0000269|PubMed:14676215, ECO:0000269|PubMed:15802564, ECO:0000269|PubMed:15967462, ECO:0000269|PubMed:16407954, ECO:0000269|PubMed:16410549, ECO:0000269|PubMed:20634290, ECO:0000269|PubMed:9645487, ECO:0000269|PubMed:9804419}.

Subcellular location: Cytoplasm {ECO:0000305|PubMed:16410549}. Nucleus {ECO:0000269|PubMed:16410549}.

Tissue specificity: Isoforms 3, 7 and 8 are expressed in cardiac muscle. Isoform 4 is expressed in vertebrate skeletal muscle. Isoform 6 is expressed in skeletal muscle (at protein level). {ECO:0000269|PubMed:11717165, ECO:0000269|PubMed:7819249}.

Domain: ZIS1 and ZIS5 regions contain multiple SPXR consensus sites for ERK- and CDK-like protein kinases as well as multiple SP motifs. ZIS1 could adopt a closed conformation which would block the TCAP-binding site.

Domain: The PEVK region may serve as an entropic spring of a chain of structural folds and may also be an interaction site to other myofilament proteins to form interfilament connectivity in the sarcomere.

Ptm: Autophosphorylated. {ECO:0000250}.

Disease: Myopathy, myofibrillar, 9, with early respiratory failure (MFM9) [MIM:603689]: An autosomal dominant myopathy characterized by adulthood onset of weakness in proximal, distal, axial and respiratory muscles. Pelvic girdle weakness, foot drop and neck weakness are the main symptoms at onset, but ultimately the weakness usually involves the proximal compartment of both upper and lower limbs. Additional features include variable degrees of Achilles tendon contractures, spinal rigidity and muscle hypertrophy. Respiratory involvement often leads to requirement for non-invasive ventilation support. {ECO:0000269|PubMed:15802564}. Note=The disease is caused by variants affecting the gene represented in this entry.

Disease: Cardiomyopathy, familial hypertrophic 9 (CMH9) [MIM:613765]: A hereditary heart disorder characterized by ventricular hypertrophy, which is usually asymmetric and often involves the interventricular septum. The symptoms include dyspnea, syncope, collapse, palpitations, and chest pain. They can be readily provoked by exercise. The disorder has inter- and intrafamilial variability ranging from benign to malignant forms with high risk of cardiac failure and sudden cardiac death. {ECO:0000269|PubMed:10462489}. Note=The disease is caused by variants affecting the gene represented in this entry.

Disease: Cardiomyopathy, dilated 1G (CMD1G) [MIM:604145]: A disorder characterized by ventricular dilation and impaired systolic function, resulting in congestive heart failure and arrhythmia. Patients are at risk of premature death. {ECO:0000269|PubMed:11788824, ECO:0000269|PubMed:11846417, ECO:0000269|PubMed:16465475}. Note=The disease is caused by variants affecting the gene represented in this entry.

Disease: Tardive tibial muscular dystrophy (TMD) [MIM:600334]: Autosomal dominant, late-onset distal myopathy. Muscle weakness and atrophy are usually confined to the anterior compartment of the lower leg, in particular the tibialis anterior muscle. Clinical symptoms usually occur at age 35-45 years or much later. {ECO:0000269|PubMed:12145747, ECO:0000269|PubMed:12891679}. Note=The disease is caused by variants affecting the gene represented in this entry.

Disease: Muscular dystrophy, limb-girdle, autosomal recessive 10 (LGMDR10) [MIM:608807]: An autosomal recessive degenerative myopathy characterized by progressive weakness of the pelvic and shoulder girdle muscles. Severe disability is observed within 20 years of onset. {ECO:0000269|PubMed:12145747}. Note=The disease is caused by variants affecting the gene represented in this entry.

Disease: Salih myopathy (SALMY) [MIM:611705]: An autosomal recessive, early-onset muscular disorder characterized by dilated cardiomyopathy, delayed motor development with generalized muscle weakness predominantly affecting proximal and distal lower limbs. Skeletal muscle biopsies show minicore-like lesions with mitochondrial depletion and sarcomere disorganization, centralized nuclei, and type 1 fiber predominance. Dystrophic changes become apparent in the second decade. Cardiac muscle biopsies show disruption of myocardial architecture, nuclear hypertrophy, and endomysial fibrosis. Sudden death may occurr due to cardiomyopathy. {ECO:0000269|PubMed:17444505}. Note=The disease is caused by variants affecting the gene represented in this entry.

Miscellaneous: In some isoforms, after the PEVK repeat region there is a long PEVK duplicated region. On account of this region, it has been very difficult to sequence the whole protein. The length of this region (ranging from 183 to 2174 residues), may be a key elastic element of titin.

Similarity: Belongs to the protein kinase superfamily. CAMK Ser/Thr protein kinase family. {ECO:0000305}.

Sequence caution: Sequence=AAH58824.1; Type=Miscellaneous discrepancy; Note=Contaminating sequence. Potential poly-A sequence starting in position 553.; Evidence={ECO:0000305}; Sequence=AAH70170.1; Type=Miscellaneous discrepancy; Note=Contaminating sequence. Potential poly-A sequence starting in position 627.; Evidence={ECO:0000305}; Sequence=CAA62188.1; Type=Frameshift; Evidence={ECO:0000305}; Sequence=CAD12455.1; Type=Frameshift; Evidence={ECO:0000305};

Annotations taken from UniProtKB at the EBI.


Organism:		Homo sapiens (Human).
Taxonomy:		Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.



Function:		Key component in the assembly and functioning of vertebrate striated muscles. By providing connections at the level of individual microfilaments, it contributes to the fine balance of forces between the two halves of the sarcomere. The size and extensibility of the cross-links are the main determinants of sarcomere extensibility properties of muscle. In non-muscle cells, seems to play a role in chromosome condensation and chromosome segregation during mitosis. Might link the lamina network to chromatin or nuclear actin, or both during interphase. {ECO:0000269\|PubMed:9804419}.


Catalytic activity:		Reaction=ATP + L-seryl-[protein] = ADP + H(+) + O-phospho-L-seryl- [protein]; Xref=Rhea:RHEA:17989, Rhea:RHEA-COMP:9863, Rhea:RHEA- COMP:11604, ChEBI:CHEBI:15378, ChEBI:CHEBI:29999, ChEBI:CHEBI:30616, ChEBI:CHEBI:83421, ChEBI:CHEBI:456216; EC=2.7.11.1;
Catalytic activity:		Reaction=ATP + L-threonyl-[protein] = ADP + H(+) + O-phospho-L- threonyl-[protein]; Xref=Rhea:RHEA:46608, Rhea:RHEA-COMP:11060, Rhea:RHEA-COMP:11605, ChEBI:CHEBI:15378, ChEBI:CHEBI:30013, ChEBI:CHEBI:30616, ChEBI:CHEBI:61977, ChEBI:CHEBI:456216; EC=2.7.11.1;
Cofactor:		Name=Mg(2+); Xref=ChEBI:CHEBI:18420;
Activity regulation:		Full activation of the protein kinase domain requires both phosphorylation of Tyr-32341, preventing it from blocking the catalytic aspartate residue, and binding of Ca/CALM to the C- terminal regulatory tail of the molecule which results in ATP binding to the kinase. {ECO:0000269\|PubMed:9804419}.
Subunit:		Interacts with MYOM1, MYOM2, tropomyosin and myosin. Interacts with actin, primarily via the PEVK domains and with MYPN (By similarity). Interacts with FHL2, NEB, CRYAB, LMNA/lamin-A and LMNB/lamin-B. Interacts with TCAP/telethonin and/or ANK1 isoform Mu17/ank1.5, via the first two N-terminal immunoglobulin domains. Interacts with TRIM63 and TRIM55, through several domains including immunoglobulin domains 141 and 142. Interacts with ANKRD1, ANKRD2 and ANKRD23, via the region between immunoglobulin domains 77 and 78 and interacts with CAPN3, via immunoglobulin domain 79. Interacts with NBR1 through the protein kinase domain. Interacts with CALM/calmodulin. Isoform 6 interacts with OBSCN isoform 3. Interacts with CMYA5. {ECO:0000250, ECO:0000269\|PubMed:11717165, ECO:0000269\|PubMed:12432079, ECO:0000269\|PubMed:12444090, ECO:0000269\|PubMed:12482578, ECO:0000269\|PubMed:14583192, ECO:0000269\|PubMed:14676215, ECO:0000269\|PubMed:15802564, ECO:0000269\|PubMed:15967462, ECO:0000269\|PubMed:16407954, ECO:0000269\|PubMed:16410549, ECO:0000269\|PubMed:20634290, ECO:0000269\|PubMed:9645487, ECO:0000269\|PubMed:9804419}.
Subcellular location:		Cytoplasm {ECO:0000305\|PubMed:16410549}. Nucleus {ECO:0000269\|PubMed:16410549}.
Tissue specificity:		Isoforms 3, 7 and 8 are expressed in cardiac muscle. Isoform 4 is expressed in vertebrate skeletal muscle. Isoform 6 is expressed in skeletal muscle (at protein level). {ECO:0000269\|PubMed:11717165, ECO:0000269\|PubMed:7819249}.
Domain:		ZIS1 and ZIS5 regions contain multiple SPXR consensus sites for ERK- and CDK-like protein kinases as well as multiple SP motifs. ZIS1 could adopt a closed conformation which would block the TCAP-binding site.
Domain:		The PEVK region may serve as an entropic spring of a chain of structural folds and may also be an interaction site to other myofilament proteins to form interfilament connectivity in the sarcomere.
Ptm:		Autophosphorylated. {ECO:0000250}.
Disease:		Myopathy, myofibrillar, 9, with early respiratory failure (MFM9) [MIM:603689]: An autosomal dominant myopathy characterized by adulthood onset of weakness in proximal, distal, axial and respiratory muscles. Pelvic girdle weakness, foot drop and neck weakness are the main symptoms at onset, but ultimately the weakness usually involves the proximal compartment of both upper and lower limbs. Additional features include variable degrees of Achilles tendon contractures, spinal rigidity and muscle hypertrophy. Respiratory involvement often leads to requirement for non-invasive ventilation support. {ECO:0000269\|PubMed:15802564}. Note=The disease is caused by variants affecting the gene represented in this entry.
Disease:		Cardiomyopathy, familial hypertrophic 9 (CMH9) [MIM:613765]: A hereditary heart disorder characterized by ventricular hypertrophy, which is usually asymmetric and often involves the interventricular septum. The symptoms include dyspnea, syncope, collapse, palpitations, and chest pain. They can be readily provoked by exercise. The disorder has inter- and intrafamilial variability ranging from benign to malignant forms with high risk of cardiac failure and sudden cardiac death. {ECO:0000269\|PubMed:10462489}. Note=The disease is caused by variants affecting the gene represented in this entry.
Disease:		Cardiomyopathy, dilated 1G (CMD1G) [MIM:604145]: A disorder characterized by ventricular dilation and impaired systolic function, resulting in congestive heart failure and arrhythmia. Patients are at risk of premature death. {ECO:0000269\|PubMed:11788824, ECO:0000269\|PubMed:11846417, ECO:0000269\|PubMed:16465475}. Note=The disease is caused by variants affecting the gene represented in this entry.
Disease:		Tardive tibial muscular dystrophy (TMD) [MIM:600334]: Autosomal dominant, late-onset distal myopathy. Muscle weakness and atrophy are usually confined to the anterior compartment of the lower leg, in particular the tibialis anterior muscle. Clinical symptoms usually occur at age 35-45 years or much later. {ECO:0000269\|PubMed:12145747, ECO:0000269\|PubMed:12891679}. Note=The disease is caused by variants affecting the gene represented in this entry.
Disease:		Muscular dystrophy, limb-girdle, autosomal recessive 10 (LGMDR10) [MIM:608807]: An autosomal recessive degenerative myopathy characterized by progressive weakness of the pelvic and shoulder girdle muscles. Severe disability is observed within 20 years of onset. {ECO:0000269\|PubMed:12145747}. Note=The disease is caused by variants affecting the gene represented in this entry.
Disease:		Salih myopathy (SALMY) [MIM:611705]: An autosomal recessive, early-onset muscular disorder characterized by dilated cardiomyopathy, delayed motor development with generalized muscle weakness predominantly affecting proximal and distal lower limbs. Skeletal muscle biopsies show minicore-like lesions with mitochondrial depletion and sarcomere disorganization, centralized nuclei, and type 1 fiber predominance. Dystrophic changes become apparent in the second decade. Cardiac muscle biopsies show disruption of myocardial architecture, nuclear hypertrophy, and endomysial fibrosis. Sudden death may occurr due to cardiomyopathy. {ECO:0000269\|PubMed:17444505}. Note=The disease is caused by variants affecting the gene represented in this entry.
Miscellaneous:		In some isoforms, after the PEVK repeat region there is a long PEVK duplicated region. On account of this region, it has been very difficult to sequence the whole protein. The length of this region (ranging from 183 to 2174 residues), may be a key elastic element of titin.
Similarity:		Belongs to the protein kinase superfamily. CAMK Ser/Thr protein kinase family. {ECO:0000305}.
Sequence caution:		Sequence=AAH58824.1; Type=Miscellaneous discrepancy; Note=Contaminating sequence. Potential poly-A sequence starting in position 553.; Evidence={ECO:0000305}; Sequence=AAH70170.1; Type=Miscellaneous discrepancy; Note=Contaminating sequence. Potential poly-A sequence starting in position 627.; Evidence={ECO:0000305}; Sequence=CAA62188.1; Type=Frameshift; Evidence={ECO:0000305}; Sequence=CAD12455.1; Type=Frameshift; Evidence={ECO:0000305};