UniProt functional annotation for Q8IZD2



	UniProt functional annotation for Q8IZD2

UniProt code: Q8IZD2.

Organism: Homo sapiens (Human).

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

Function: Associates with chromatin regions downstream of transcriptional start sites of active genes and thus regulates gene transcription (PubMed:23629655, PubMed:24130829, PubMed:23798402). Chromatin interaction is mediated via the binding to tri-methylated histone H3 at 'Lys-4' (H3K4me3) (PubMed:24130829, PubMed:23798402). Key regulator of hematopoiesis involved in terminal myeloid differentiation and in the regulation of hematopoietic stem cell (HSCs) self-renewal by a mechanism that involves DNA methylation (By similarity). Also acts as an important cell cycle regulator, participating in cell cycle regulatory network machinery at multiple cell cycle stages including G1/S transition, S phase progression and mitotic entry (PubMed:14718661, PubMed:18573682, PubMed:19264965, PubMed:23629655). Recruited to E2F1 responsive promoters by HCFC1 where it stimulates tri-methylation of histone H3 at 'Lys-4' and transcriptional activation and thereby facilitates G1 to S phase transition (PubMed:23629655). During myoblast differentiation, required to suppress inappropriate expression of S-phase-promoting genes and maintain expression of determination genes in quiescent cells (By similarity). {ECO:0000250|UniProtKB:Q3UG20, ECO:0000269|PubMed:14718661, ECO:0000269|PubMed:18573682, ECO:0000269|PubMed:23629655, ECO:0000269|PubMed:23798402, ECO:0000269|PubMed:24130829}.

Function: [Isoform NKp44L]: Cellular ligand for NCR2/NKp44, may play a role as a danger signal in cytotoxicity and NK-cell-mediated innate immunity. {ECO:0000269|PubMed:23958951}.

Subunit: Component of a complex composed of KMT2E (isoform 3), OGT and USP7; the complex stabilizes KMT2E, preventing KMT2E ubiquitination and proteosomal-mediated degradation (PubMed:26678539). Isoform 3 interacts (via N-terminus) with OGT (via TRP repeats) (PubMed:26678539, PubMed:23629655). Isoform 3 interacts with deubiquitinating enzyme USP7 (via MATH domain) (PubMed:26678539). Isoform 3 interacts (via HBM motif) with HCFC1 (via Kelch domain) (PubMed:23629655). Isoform 3 interacts with E2F1; the interaction is probably indirect and is mediated via HCFC1 (PubMed:23629655). {ECO:0000269|PubMed:23629655, ECO:0000269|PubMed:26678539}.

Subcellular location: Chromosome {ECO:0000269|PubMed:23798402}. Cytoplasm, cytoskeleton, microtubule organizing center, centrosome {ECO:0000269|PubMed:23798402}. Nucleus speckle {ECO:0000269|PubMed:14718661}. Note=Absent from the nucleolus (PubMed:14718661). Localizes to chromosome during interphase and to centrosomes during mitosis (PubMed:23798402). Dissociation from mitotic chromosome is likely due to histone H3 phosphorylation on 'Thr-3' and 'Thr-6' (PubMed:23798402). {ECO:0000269|PubMed:14718661, ECO:0000269|PubMed:23798402}.

Subcellular location: [Isoform 3]: Nucleus, nucleoplasm {ECO:0000269|PubMed:23629655, ECO:0000269|PubMed:26678539}. Nucleus speckle {ECO:0000269|PubMed:23798402}. Note=Absent from the nucleolus (PubMed:23629655). Localizes to chromosome during interphase and to nucleus speckle during mitosis (PubMed:23798402). Dissociation from mitotic chromosome is likely due to histone H3 phosphorylation on 'Thr- 3' and 'Thr-6' (PubMed:23798402). {ECO:0000269|PubMed:23629655, ECO:0000269|PubMed:23798402}.

Subcellular location: [Isoform NKp44L]: Cytoplasm {ECO:0000269|PubMed:23958951}. Cell membrane {ECO:0000269|PubMed:23958951}; Peripheral membrane protein {ECO:0000269|PubMed:23958951}.

Tissue specificity: Widely expressed in both adult and fetal tissues (PubMed:12101424, PubMed:23958951). Highest levels of expression observed in fetal thymus and kidney and in adult hematopoietic tissues, jejunum and cerebellum (PubMed:12101424, PubMed:23958951). Isoform NKp44L: Not detected on circulating cells from healthy individuals, but is expressed on a large panel of tumor and transformed cells (PubMed:23958951). {ECO:0000269|PubMed:12101424, ECO:0000269|PubMed:23958951}.

Domain: The PHD-type domain binds specifically histone H3 tri- methylated at 'Lys-4' (H3K4me3), thus promoting binding to chromatin. {ECO:0000269|PubMed:23798402, ECO:0000269|PubMed:24130829}.

Domain: The SET domain does not bind the methyl group donor S-adenosyl- L-methionine and histone 3 H3K4 peptide as a large loop prevents the docking of the 'Lys-4' side chain. {ECO:0000269|PubMed:27812132}.

Domain: The C-terminus domain is responsible for the localization to the centrosome during mitosis. {ECO:0000269|PubMed:23798402}.

Ptm: Ubiquitinated. Deubiquitinated by USP7. {ECO:0000269|PubMed:26678539}.

Ptm: O-glycosylated at Ser-435 and Thr-440 in the SET domain by OGT which probably prevents KMT2E proteasomal-mediated degradation. {ECO:0000269|PubMed:26678539}.

Disease: O'Donnell-Luria-Rodan syndrome (ODLURO) [MIM:618512]: A neurodevelopmental disorder characterized by global developmental delay, speech delay, intellectual disability and a subtle facial gestalt. Additional common features include autism, seizures, hypotonia and functional gastrointestinal abnormalities. {ECO:0000269|PubMed:31079897}. Note=The disease is caused by variants affecting the gene represented in this entry.

Similarity: Belongs to the class V-like SAM-binding methyltransferase superfamily. Histone-lysine methyltransferase family. TRX/MLL subfamily. {ECO:0000255|PROSITE-ProRule:PRU00190}.

Sequence caution: Sequence=AAH01296.1; Type=Miscellaneous discrepancy; Note=Contaminating sequence. Potential poly-A sequence starting in position 492.; Evidence={ECO:0000305}; Sequence=AAH40004.1; Type=Miscellaneous discrepancy; Note=Contaminating sequence. Potential poly-A sequence starting in position 227.; Evidence={ECO:0000305}; Sequence=AAH53906.1; Type=Miscellaneous discrepancy; Note=Contaminating sequence. Potential poly-A sequence starting in position 227.; Evidence={ECO:0000305}; Sequence=AAI42988.1; Type=Miscellaneous discrepancy; Note=Contaminating sequence. Potential poly-A sequence starting in position 492.; 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:		Associates with chromatin regions downstream of transcriptional start sites of active genes and thus regulates gene transcription (PubMed:23629655, PubMed:24130829, PubMed:23798402). Chromatin interaction is mediated via the binding to tri-methylated histone H3 at 'Lys-4' (H3K4me3) (PubMed:24130829, PubMed:23798402). Key regulator of hematopoiesis involved in terminal myeloid differentiation and in the regulation of hematopoietic stem cell (HSCs) self-renewal by a mechanism that involves DNA methylation (By similarity). Also acts as an important cell cycle regulator, participating in cell cycle regulatory network machinery at multiple cell cycle stages including G1/S transition, S phase progression and mitotic entry (PubMed:14718661, PubMed:18573682, PubMed:19264965, PubMed:23629655). Recruited to E2F1 responsive promoters by HCFC1 where it stimulates tri-methylation of histone H3 at 'Lys-4' and transcriptional activation and thereby facilitates G1 to S phase transition (PubMed:23629655). During myoblast differentiation, required to suppress inappropriate expression of S-phase-promoting genes and maintain expression of determination genes in quiescent cells (By similarity). {ECO:0000250\|UniProtKB:Q3UG20, ECO:0000269\|PubMed:14718661, ECO:0000269\|PubMed:18573682, ECO:0000269\|PubMed:23629655, ECO:0000269\|PubMed:23798402, ECO:0000269\|PubMed:24130829}.



Function:		[Isoform NKp44L]: Cellular ligand for NCR2/NKp44, may play a role as a danger signal in cytotoxicity and NK-cell-mediated innate immunity. {ECO:0000269\|PubMed:23958951}.


Subunit:		Component of a complex composed of KMT2E (isoform 3), OGT and USP7; the complex stabilizes KMT2E, preventing KMT2E ubiquitination and proteosomal-mediated degradation (PubMed:26678539). Isoform 3 interacts (via N-terminus) with OGT (via TRP repeats) (PubMed:26678539, PubMed:23629655). Isoform 3 interacts with deubiquitinating enzyme USP7 (via MATH domain) (PubMed:26678539). Isoform 3 interacts (via HBM motif) with HCFC1 (via Kelch domain) (PubMed:23629655). Isoform 3 interacts with E2F1; the interaction is probably indirect and is mediated via HCFC1 (PubMed:23629655). {ECO:0000269\|PubMed:23629655, ECO:0000269\|PubMed:26678539}.
Subcellular location:		Chromosome {ECO:0000269\|PubMed:23798402}. Cytoplasm, cytoskeleton, microtubule organizing center, centrosome {ECO:0000269\|PubMed:23798402}. Nucleus speckle {ECO:0000269\|PubMed:14718661}. Note=Absent from the nucleolus (PubMed:14718661). Localizes to chromosome during interphase and to centrosomes during mitosis (PubMed:23798402). Dissociation from mitotic chromosome is likely due to histone H3 phosphorylation on 'Thr-3' and 'Thr-6' (PubMed:23798402). {ECO:0000269\|PubMed:14718661, ECO:0000269\|PubMed:23798402}.
Subcellular location:		[Isoform 3]: Nucleus, nucleoplasm {ECO:0000269\|PubMed:23629655, ECO:0000269\|PubMed:26678539}. Nucleus speckle {ECO:0000269\|PubMed:23798402}. Note=Absent from the nucleolus (PubMed:23629655). Localizes to chromosome during interphase and to nucleus speckle during mitosis (PubMed:23798402). Dissociation from mitotic chromosome is likely due to histone H3 phosphorylation on 'Thr- 3' and 'Thr-6' (PubMed:23798402). {ECO:0000269\|PubMed:23629655, ECO:0000269\|PubMed:23798402}.
Subcellular location:		[Isoform NKp44L]: Cytoplasm {ECO:0000269\|PubMed:23958951}. Cell membrane {ECO:0000269\|PubMed:23958951}; Peripheral membrane protein {ECO:0000269\|PubMed:23958951}.
Tissue specificity:		Widely expressed in both adult and fetal tissues (PubMed:12101424, PubMed:23958951). Highest levels of expression observed in fetal thymus and kidney and in adult hematopoietic tissues, jejunum and cerebellum (PubMed:12101424, PubMed:23958951). Isoform NKp44L: Not detected on circulating cells from healthy individuals, but is expressed on a large panel of tumor and transformed cells (PubMed:23958951). {ECO:0000269\|PubMed:12101424, ECO:0000269\|PubMed:23958951}.
Domain:		The PHD-type domain binds specifically histone H3 tri- methylated at 'Lys-4' (H3K4me3), thus promoting binding to chromatin. {ECO:0000269\|PubMed:23798402, ECO:0000269\|PubMed:24130829}.
Domain:		The SET domain does not bind the methyl group donor S-adenosyl- L-methionine and histone 3 H3K4 peptide as a large loop prevents the docking of the 'Lys-4' side chain. {ECO:0000269\|PubMed:27812132}.
Domain:		The C-terminus domain is responsible for the localization to the centrosome during mitosis. {ECO:0000269\|PubMed:23798402}.
Ptm:		Ubiquitinated. Deubiquitinated by USP7. {ECO:0000269\|PubMed:26678539}.
Ptm:		O-glycosylated at Ser-435 and Thr-440 in the SET domain by OGT which probably prevents KMT2E proteasomal-mediated degradation. {ECO:0000269\|PubMed:26678539}.
Disease:		O'Donnell-Luria-Rodan syndrome (ODLURO) [MIM:618512]: A neurodevelopmental disorder characterized by global developmental delay, speech delay, intellectual disability and a subtle facial gestalt. Additional common features include autism, seizures, hypotonia and functional gastrointestinal abnormalities. {ECO:0000269\|PubMed:31079897}. Note=The disease is caused by variants affecting the gene represented in this entry.
Similarity:		Belongs to the class V-like SAM-binding methyltransferase superfamily. Histone-lysine methyltransferase family. TRX/MLL subfamily. {ECO:0000255\|PROSITE-ProRule:PRU00190}.
Sequence caution:		Sequence=AAH01296.1; Type=Miscellaneous discrepancy; Note=Contaminating sequence. Potential poly-A sequence starting in position 492.; Evidence={ECO:0000305}; Sequence=AAH40004.1; Type=Miscellaneous discrepancy; Note=Contaminating sequence. Potential poly-A sequence starting in position 227.; Evidence={ECO:0000305}; Sequence=AAH53906.1; Type=Miscellaneous discrepancy; Note=Contaminating sequence. Potential poly-A sequence starting in position 227.; Evidence={ECO:0000305}; Sequence=AAI42988.1; Type=Miscellaneous discrepancy; Note=Contaminating sequence. Potential poly-A sequence starting in position 492.; Evidence={ECO:0000305};