UniProt functional annotation for Q4ACU6



	UniProt functional annotation for Q4ACU6

UniProt code: Q4ACU6.

Organism: Mus musculus (Mouse).

Taxonomy: Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae; Murinae; Mus; Mus.

Function: Major scaffold postsynaptic density protein which interacts with multiple proteins and complexes to orchestrate the dendritic spine and synapse formation, maturation and maintenance. Interconnects receptors of the postsynaptic membrane including NMDA-type and metabotropic glutamate receptors via complexes with GKAP/PSD-95 and HOMER, respectively, and the actin-based cytoskeleton. Plays a role in the structural and functional organization of the dendritic spine and synaptic junction through the interaction with Arp2/3 and WAVE1 complex as well as the promotion of the F-actin clusters. By way of this control of actin dynamics, participates in the regulation of developing neurons growth cone motility and the NMDA receptor-signaling. Also modulates GRIA1 exocytosis and GRM5/MGLUR5 expression and signaling to control the AMPA and metabotropic glutamate receptor-mediated synaptic transmission and plasticity. May be required at an early stage of synapse formation and be inhibited by IGF1 to promote synapse maturation. {ECO:0000269|PubMed:21423165, ECO:0000269|PubMed:21558424, ECO:0000269|PubMed:23739967, ECO:0000269|PubMed:24153177}.

Subunit: May homomultimerize via its SAM domain. Interacts with BAIAP2, DBNL and SLC17A7/VGLUT1. Interacts with DLGAP1/GKAP, GRM1/MGLUR1, GRM5/MGLUR5 and LZTS3 C-termini via its PDZ domain. Interacts with ABI1, HOMER1, HOMER2, HOMER3 and CTTN/cortactin SH3 domain. Is part of a complex with DLG4/PSD-95 and DLGAP1/GKAP. Interacts (via PDZ domain) with the GRIA1 subunit of the AMPA receptor (via PDZ-binding motif). Interacts with WASF1 and CYFIP2; the interactions mediate the association of SHANK3 with the WAVE1 complex. Interacts with ARPC2; the interaction probably mediates the association of SHANK3 with the Arp2/3 complex. Interacts (via ANK repeats) with SHARPIN and SPTAN1. Interacts (via PDZ domain) with ARHGAP44 (probably via PDZ-binding motif); the interaction takes place in dendritic spines and promotes GRIA1 exocytosis. Interacts with CAMK2A (By similarity). Interacts with DIP2A (PubMed:31600191). {ECO:0000250|UniProtKB:Q9BYB0, ECO:0000269|PubMed:16606358, ECO:0000269|PubMed:21558424, ECO:0000269|PubMed:23739967, ECO:0000269|PubMed:24153177, ECO:0000269|PubMed:31600191}.

Subcellular location: Cytoplasm. Cell junction, synapse. Cell junction, synapse, postsynaptic density. Cell projection, dendritic spine {ECO:0000250}. Note=In neuronal cells, extends into the region subjacent to the postsynaptic density (PSD).

Tissue specificity: In brain, highly expressed in striatum, thalamus, hippocampus and granule cells of the cerebellum. {ECO:0000269|PubMed:21423165, ECO:0000269|PubMed:21558424, ECO:0000269|PubMed:24153177}.

Developmental stage: Isoform 3 is weakly expressed at 17 dpc but its expression increases after birth. {ECO:0000269|PubMed:24164323}.

Domain: In isoform 1, the N-terminal region preceding the ANK repeats interacts with the 6 ANK repeats in an intramolecular manner, thereby restricting access to ligands, such as SHARPIN and SPTAN1. {ECO:0000250}.

Disruption phenotype: Animals deficient for isoforms 1-7 exhibit self- injourious repetitive grooming and deficits in social interaction. They show defects at striatal synapses and cortico-striatal circuits with an increase in striatal volume, dendritic length, and surface area and a decrease of spine density, length and thickness of PSD. They seem to have an altered molecular composition of postsynaptic machinery in the striatum (PubMed:21423165). In contrast, animals deficient for isoforms 1 and 2 exhibit a normal initiation of social interaction with a perturbed recognition of social novelty (PubMed:21423165). In PubMed:21558424, animals deficient for isoforms 1 and 2 show abnormal social behaviors, communication patterns, repetitive behaviors, learning and memory. In CA1 hippocampus, the synaptic plasticity is impaired with longer dendritic spines, decreased spine density and deficient long-term potentiation. The expression of specific synaptic scaffolding proteins and receptor subunits are altered. Animals deficient for isoforms 1-5 exhibit self-injourious repetitive grooming, brain-region-specific up-regulation of ionotropic glutamate receptors and increased levels of SHANK2 (PubMed:22699619). Animals deficient for predominant isoforms containing exon 21 exhibit motor-coordination deficits, hypersensitivity to heat, novelty avoidance, altered locomotor response to novelty and minimal social abnormalities. They show a decrease in NMDA-AMPA excitatory postsynaptic current ratio in hippocampal CA1, reduced long-term potentiation and deficits in hippocampus-dependent spatial learning and memory (PubMed:24259569). {ECO:0000269|PubMed:21423165, ECO:0000269|PubMed:21558424, ECO:0000269|PubMed:22699619, ECO:0000269|PubMed:24259569}.

Miscellaneous: [Isoform 2]: Produced by alternative promoter usage and alternative splicing. {ECO:0000305}.

Miscellaneous: [Isoform 4]: Produced by alternative splicing of isoform 3. {ECO:0000305}.

Miscellaneous: [Isoform 5]: Produced by alternative splicing of isoform 3. {ECO:0000305}.

Miscellaneous: [Isoform 6]: Produced by alternative promoter usage. {ECO:0000305}.

Miscellaneous: [Isoform 7]: Produced by alternative splicing of isoform 6. {ECO:0000305}.

Miscellaneous: [Isoform 8]: Produced by alternative promoter usage. {ECO:0000305}.

Miscellaneous: [Isoform 9]: Produced by alternative splicing of isoform 8. {ECO:0000305}.

Miscellaneous: [Isoform 3]: Produced by alternative promoter usage. {ECO:0000305}.

Miscellaneous: [Isoform 10]: Produced by alternative promoter usage. {ECO:0000305}.

Similarity: Belongs to the SHANK family. {ECO:0000305}.

Annotations taken from UniProtKB at the EBI.


Organism:		Mus musculus (Mouse).
Taxonomy:		Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae; Murinae; Mus; Mus.



Function:		Major scaffold postsynaptic density protein which interacts with multiple proteins and complexes to orchestrate the dendritic spine and synapse formation, maturation and maintenance. Interconnects receptors of the postsynaptic membrane including NMDA-type and metabotropic glutamate receptors via complexes with GKAP/PSD-95 and HOMER, respectively, and the actin-based cytoskeleton. Plays a role in the structural and functional organization of the dendritic spine and synaptic junction through the interaction with Arp2/3 and WAVE1 complex as well as the promotion of the F-actin clusters. By way of this control of actin dynamics, participates in the regulation of developing neurons growth cone motility and the NMDA receptor-signaling. Also modulates GRIA1 exocytosis and GRM5/MGLUR5 expression and signaling to control the AMPA and metabotropic glutamate receptor-mediated synaptic transmission and plasticity. May be required at an early stage of synapse formation and be inhibited by IGF1 to promote synapse maturation. {ECO:0000269\|PubMed:21423165, ECO:0000269\|PubMed:21558424, ECO:0000269\|PubMed:23739967, ECO:0000269\|PubMed:24153177}.


Subunit:		May homomultimerize via its SAM domain. Interacts with BAIAP2, DBNL and SLC17A7/VGLUT1. Interacts with DLGAP1/GKAP, GRM1/MGLUR1, GRM5/MGLUR5 and LZTS3 C-termini via its PDZ domain. Interacts with ABI1, HOMER1, HOMER2, HOMER3 and CTTN/cortactin SH3 domain. Is part of a complex with DLG4/PSD-95 and DLGAP1/GKAP. Interacts (via PDZ domain) with the GRIA1 subunit of the AMPA receptor (via PDZ-binding motif). Interacts with WASF1 and CYFIP2; the interactions mediate the association of SHANK3 with the WAVE1 complex. Interacts with ARPC2; the interaction probably mediates the association of SHANK3 with the Arp2/3 complex. Interacts (via ANK repeats) with SHARPIN and SPTAN1. Interacts (via PDZ domain) with ARHGAP44 (probably via PDZ-binding motif); the interaction takes place in dendritic spines and promotes GRIA1 exocytosis. Interacts with CAMK2A (By similarity). Interacts with DIP2A (PubMed:31600191). {ECO:0000250\|UniProtKB:Q9BYB0, ECO:0000269\|PubMed:16606358, ECO:0000269\|PubMed:21558424, ECO:0000269\|PubMed:23739967, ECO:0000269\|PubMed:24153177, ECO:0000269\|PubMed:31600191}.
Subcellular location:		Cytoplasm. Cell junction, synapse. Cell junction, synapse, postsynaptic density. Cell projection, dendritic spine {ECO:0000250}. Note=In neuronal cells, extends into the region subjacent to the postsynaptic density (PSD).
Tissue specificity:		In brain, highly expressed in striatum, thalamus, hippocampus and granule cells of the cerebellum. {ECO:0000269\|PubMed:21423165, ECO:0000269\|PubMed:21558424, ECO:0000269\|PubMed:24153177}.
Developmental stage:		Isoform 3 is weakly expressed at 17 dpc but its expression increases after birth. {ECO:0000269\|PubMed:24164323}.
Domain:		In isoform 1, the N-terminal region preceding the ANK repeats interacts with the 6 ANK repeats in an intramolecular manner, thereby restricting access to ligands, such as SHARPIN and SPTAN1. {ECO:0000250}.
Disruption phenotype:		Animals deficient for isoforms 1-7 exhibit self- injourious repetitive grooming and deficits in social interaction. They show defects at striatal synapses and cortico-striatal circuits with an increase in striatal volume, dendritic length, and surface area and a decrease of spine density, length and thickness of PSD. They seem to have an altered molecular composition of postsynaptic machinery in the striatum (PubMed:21423165). In contrast, animals deficient for isoforms 1 and 2 exhibit a normal initiation of social interaction with a perturbed recognition of social novelty (PubMed:21423165). In PubMed:21558424, animals deficient for isoforms 1 and 2 show abnormal social behaviors, communication patterns, repetitive behaviors, learning and memory. In CA1 hippocampus, the synaptic plasticity is impaired with longer dendritic spines, decreased spine density and deficient long-term potentiation. The expression of specific synaptic scaffolding proteins and receptor subunits are altered. Animals deficient for isoforms 1-5 exhibit self-injourious repetitive grooming, brain-region-specific up-regulation of ionotropic glutamate receptors and increased levels of SHANK2 (PubMed:22699619). Animals deficient for predominant isoforms containing exon 21 exhibit motor-coordination deficits, hypersensitivity to heat, novelty avoidance, altered locomotor response to novelty and minimal social abnormalities. They show a decrease in NMDA-AMPA excitatory postsynaptic current ratio in hippocampal CA1, reduced long-term potentiation and deficits in hippocampus-dependent spatial learning and memory (PubMed:24259569). {ECO:0000269\|PubMed:21423165, ECO:0000269\|PubMed:21558424, ECO:0000269\|PubMed:22699619, ECO:0000269\|PubMed:24259569}.
Miscellaneous:		[Isoform 2]: Produced by alternative promoter usage and alternative splicing. {ECO:0000305}.
Miscellaneous:		[Isoform 4]: Produced by alternative splicing of isoform 3. {ECO:0000305}.
Miscellaneous:		[Isoform 5]: Produced by alternative splicing of isoform 3. {ECO:0000305}.
Miscellaneous:		[Isoform 6]: Produced by alternative promoter usage. {ECO:0000305}.
Miscellaneous:		[Isoform 7]: Produced by alternative splicing of isoform 6. {ECO:0000305}.
Miscellaneous:		[Isoform 8]: Produced by alternative promoter usage. {ECO:0000305}.
Miscellaneous:		[Isoform 9]: Produced by alternative splicing of isoform 8. {ECO:0000305}.
Miscellaneous:		[Isoform 3]: Produced by alternative promoter usage. {ECO:0000305}.
Miscellaneous:		[Isoform 10]: Produced by alternative promoter usage. {ECO:0000305}.
Similarity:		Belongs to the SHANK family. {ECO:0000305}.