UniProt functional annotation for O14936



	UniProt functional annotation for O14936

UniProt code: O14936.

Organism: Homo sapiens (Human).

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

Function: Multidomain scaffolding protein with a role in synaptic transmembrane protein anchoring and ion channel trafficking. Contributes to neural development and regulation of gene expression via interaction with the transcription factor TBR1. Binds to cell-surface proteins, including amyloid precursor protein, neurexins and syndecans. May mediate a link between the extracellular matrix and the actin cytoskeleton via its interaction with syndecan and with the actin/spectrin-binding protein 4.1. Component of the LIN-10-LIN-2-LIN-7 complex, which associates with the motor protein KIF17 to transport vesicles containing N-methyl-D-aspartate (NMDA) receptor subunit NR2B along microtubules (By similarity). {ECO:0000250|UniProtKB:O70589}.

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: Note=Unlike other protein kinases, does not require a divalent cation such as magnesium for catalytic activity. {ECO:0000269|PubMed:18423203};

Activity regulation: Differs from archetypal CaMK members in that the kinase domain exhibits a constitutively active conformation and the autoinhibitory region does not engage in direct contact with the ATP- binding cleft, although it still binds Ca(2+)/CAM. {ECO:0000269|PubMed:18423203}.

Biophysicochemical properties: Kinetic parameters: KM=563 uM for ATP {ECO:0000269|PubMed:18423203}; Note=Kinetics of autophosphorylation assay were measured, rather than phosphorylation of an exogenous substrate.;

Subunit: CASK and LIN7 form two mutually exclusive tripartite complexes with APBA1 or CASKIN1 (By similarity). Component of the brain-specific heterotrimeric complex (LIN-10-LIN-2-LIN-7 complex) composed of at least APBA1, CASK, and LIN7, which associates with the motor protein KIF17 to transport vesicles along microtubules (By similarity). Forms a heterotrimeric complex with DLG1 and LIN7B via their L27 domains (By similarity). Identified in a complex with ACTN4, IQGAP1, MAGI2, NPHS1, SPTAN1 and SPTBN1 (By similarity). Part of a complex containing CASK, TBR1 and TSPYL2 (By similarity). Interacts with WHRN (By similarity). Interacts (via the PDZ, SH3 and guanylate kinase-like domains) with NRXN1 (via C-terminus) (By similarity). Interacts with CASKIN1, APBA1, LIN7(A/B/C) and L27 domain of DLG1 and isoform 2 of DLG4 (By similarity). Interacts with FCHSD2 (By similarity). Interacts with KIRREL3 (PubMed:19012874). Interacts with TBR1 (By similarity). Interacts with TSPYL2 (By similarity). {ECO:0000250, ECO:0000250|UniProtKB:O70589, ECO:0000250|UniProtKB:Q62915, ECO:0000269|PubMed:18423203, ECO:0000269|PubMed:19012874, ECO:0000269|PubMed:9660868}.

Subcellular location: Nucleus {ECO:0000250|UniProtKB:Q62915}. Cytoplasm {ECO:0000250|UniProtKB:Q62915}. Cell membrane {ECO:0000250|UniProtKB:Q62915}; Peripheral membrane protein {ECO:0000250|UniProtKB:Q62915}.

Tissue specificity: Ubiquitous. Expression is significantly greater in brain relative to kidney, lung, and liver and in fetal brain and kidney relative to lung and liver. {ECO:0000269|PubMed:11003712}.

Domain: The first L27 domain binds DLG1 and the second L27 domain probably binds LIN7. {ECO:0000250}.

Domain: The protein kinase domain mediates the interaction with FCHSD2.

Disease: Mental retardation and microcephaly with pontine and cerebellar hypoplasia (MICPCH) [MIM:300749]: A disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. Affected individuals can manifest a severe phenotype consisting of severe intellectual deficit, congenital or postnatal microcephaly, disproportionate brainstem and cerebellar hypoplasia. A milder phenotype consists of mental retardation alone or associated with nystagmus. {ECO:0000269|PubMed:19165920, ECO:0000269|PubMed:19377476}. Note=The disease is caused by variants affecting the gene represented in this entry.

Disease: FG syndrome 4 (FGS4) [MIM:300422]: FG syndrome (FGS) is an X- linked disorder characterized by mental retardation, relative macrocephaly, hypotonia and constipation. {ECO:0000269|PubMed:19200522}. Note=The disease is caused by variants affecting the gene represented in this entry.

Similarity: In the N-terminal section; belongs to the protein kinase superfamily. CAMK Ser/Thr protein kinase family. CaMK subfamily. {ECO:0000305}.

Similarity: Belongs to the MAGUK family. {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:		Multidomain scaffolding protein with a role in synaptic transmembrane protein anchoring and ion channel trafficking. Contributes to neural development and regulation of gene expression via interaction with the transcription factor TBR1. Binds to cell-surface proteins, including amyloid precursor protein, neurexins and syndecans. May mediate a link between the extracellular matrix and the actin cytoskeleton via its interaction with syndecan and with the actin/spectrin-binding protein 4.1. Component of the LIN-10-LIN-2-LIN-7 complex, which associates with the motor protein KIF17 to transport vesicles containing N-methyl-D-aspartate (NMDA) receptor subunit NR2B along microtubules (By similarity). {ECO:0000250\|UniProtKB:O70589}.


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:		Note=Unlike other protein kinases, does not require a divalent cation such as magnesium for catalytic activity. {ECO:0000269\|PubMed:18423203};
Activity regulation:		Differs from archetypal CaMK members in that the kinase domain exhibits a constitutively active conformation and the autoinhibitory region does not engage in direct contact with the ATP- binding cleft, although it still binds Ca(2+)/CAM. {ECO:0000269\|PubMed:18423203}.
Biophysicochemical properties:		Kinetic parameters: KM=563 uM for ATP {ECO:0000269\|PubMed:18423203}; Note=Kinetics of autophosphorylation assay were measured, rather than phosphorylation of an exogenous substrate.;
Subunit:		CASK and LIN7 form two mutually exclusive tripartite complexes with APBA1 or CASKIN1 (By similarity). Component of the brain-specific heterotrimeric complex (LIN-10-LIN-2-LIN-7 complex) composed of at least APBA1, CASK, and LIN7, which associates with the motor protein KIF17 to transport vesicles along microtubules (By similarity). Forms a heterotrimeric complex with DLG1 and LIN7B via their L27 domains (By similarity). Identified in a complex with ACTN4, IQGAP1, MAGI2, NPHS1, SPTAN1 and SPTBN1 (By similarity). Part of a complex containing CASK, TBR1 and TSPYL2 (By similarity). Interacts with WHRN (By similarity). Interacts (via the PDZ, SH3 and guanylate kinase-like domains) with NRXN1 (via C-terminus) (By similarity). Interacts with CASKIN1, APBA1, LIN7(A/B/C) and L27 domain of DLG1 and isoform 2 of DLG4 (By similarity). Interacts with FCHSD2 (By similarity). Interacts with KIRREL3 (PubMed:19012874). Interacts with TBR1 (By similarity). Interacts with TSPYL2 (By similarity). {ECO:0000250, ECO:0000250\|UniProtKB:O70589, ECO:0000250\|UniProtKB:Q62915, ECO:0000269\|PubMed:18423203, ECO:0000269\|PubMed:19012874, ECO:0000269\|PubMed:9660868}.
Subcellular location:		Nucleus {ECO:0000250\|UniProtKB:Q62915}. Cytoplasm {ECO:0000250\|UniProtKB:Q62915}. Cell membrane {ECO:0000250\|UniProtKB:Q62915}; Peripheral membrane protein {ECO:0000250\|UniProtKB:Q62915}.
Tissue specificity:		Ubiquitous. Expression is significantly greater in brain relative to kidney, lung, and liver and in fetal brain and kidney relative to lung and liver. {ECO:0000269\|PubMed:11003712}.
Domain:		The first L27 domain binds DLG1 and the second L27 domain probably binds LIN7. {ECO:0000250}.
Domain:		The protein kinase domain mediates the interaction with FCHSD2.
Disease:		Mental retardation and microcephaly with pontine and cerebellar hypoplasia (MICPCH) [MIM:300749]: A disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. Affected individuals can manifest a severe phenotype consisting of severe intellectual deficit, congenital or postnatal microcephaly, disproportionate brainstem and cerebellar hypoplasia. A milder phenotype consists of mental retardation alone or associated with nystagmus. {ECO:0000269\|PubMed:19165920, ECO:0000269\|PubMed:19377476}. Note=The disease is caused by variants affecting the gene represented in this entry.
Disease:		FG syndrome 4 (FGS4) [MIM:300422]: FG syndrome (FGS) is an X- linked disorder characterized by mental retardation, relative macrocephaly, hypotonia and constipation. {ECO:0000269\|PubMed:19200522}. Note=The disease is caused by variants affecting the gene represented in this entry.
Similarity:		In the N-terminal section; belongs to the protein kinase superfamily. CAMK Ser/Thr protein kinase family. CaMK subfamily. {ECO:0000305}.
Similarity:		Belongs to the MAGUK family. {ECO:0000305}.