Neurogenic locus notch homolog protein 4

Last updated
NOTCH4
Identifiers
Aliases NOTCH4 , INT3, notch 4
External IDs MGI: 107471 HomoloGene: 3351 GeneCards: NOTCH4
Gene location (Human)
Ideogram human chromosome 6.svg
Chr. Chromosome 6 (human) [1]
Human chromosome 6 ideogram.svg
HSR 1996 II 3.5e.svg
Red rectangle 2x18.png
Band 6p21.32Start32,194,843 bp [1]
End32,224,067 bp [1]
Orthologs
SpeciesHumanMouse
Entrez

4855

18132

Ensembl

ENSMUSG00000015468

UniProt

Q99466

P31695

RefSeq (mRNA)

NM_004557

NM_010929

RefSeq (protein)

NP_004548

NP_035059

Location (UCSC) Chr 6: 32.19 – 32.22 Mb Chr 17: 34.56 – 34.59 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Neurogenic locus notch homolog 4 also known as notch 4 is a protein that in humans is encoded by the NOTCH4 gene located on chromosome 6. [5]

Protein biological molecule consisting of chains of amino acid residues

Proteins are large biomolecules, or macromolecules, consisting of one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, responding to stimuli, providing structure to cells and organisms, and transporting molecules from one location to another. Proteins differ from one another primarily in their sequence of amino acids, which is dictated by the nucleotide sequence of their genes, and which usually results in protein folding into a specific three-dimensional structure that determines its activity.

Gene Basic physical and functional unit of heredity

In biology, a gene is a sequence of nucleotides in DNA or RNA that codes for a molecule that has a function. During gene expression, the DNA is first copied into RNA. The RNA can be directly functional or be the intermediate template for a protein that performs a function. The transmission of genes to an organism's offspring is the basis of the inheritance of phenotypic trait. These genes make up different DNA sequences called genotypes. Genotypes along with environmental and developmental factors determine what the phenotypes will be. Most biological traits are under the influence of polygenes as well as gene–environment interactions. Some genetic traits are instantly visible, such as eye color or number of limbs, and some are not, such as blood type, risk for specific diseases, or the thousands of basic biochemical processes that constitute life.

Contents

Gene

An alternative splice variant of the NOTCH4 gene has been described, but its biological significance has not been determined. [6]

Alternative splicing Process by which a single gene can code for multiple proteins

Alternative splicing, or differential splicing, is a regulated process during gene expression that results in a single gene coding for multiple proteins. In this process, particular exons of a gene may be included within or excluded from the final, processed messenger RNA (mRNA) produced from that gene. Consequently, the proteins translated from alternatively spliced mRNAs will contain differences in their amino acid sequence and, often, in their biological functions. Notably, alternative splicing allows the human genome to direct the synthesis of many more proteins than would be expected from its 20,000 protein-coding genes.

Structure

The neurogenic locus notch homolog 4 protein is a member of the Notch family. Members of this type 1 transmembrane protein family share structural characteristics. These include an extracellular domain consisting of multiple epidermal growth factor-like (EGF) repeats, and an intracellular domain that consists of multiple, but different, domain types.

Notch proteins

Notch proteins are a family of Type-1 transmembrane proteins that form a core component of the Notch signaling pathway, which is highly conserved in metazoans. The Notch extracellular domain (NECD) mediates interactions with DSL family ligands, allowing it to participate in juxtacrine signaling.The Notch intracellular domain (NICD) acts as a transcriptional activator when in complex with CSL family transcription factors. Members of this Type 1 transmembrane protein family share several core structures, including an extracellular domain consisting of multiple epidermal growth factor (EGF)-like repeats and an intracellular domain transcriptional activation domain (TAD). Notch family members operate in a variety of different tissues and play a role in a variety of developmental processes by controlling cell fate decisions. Much of what is known about Notch function comes from studies done in Caenorhabditis elegans (C.elegans) and Drosophila melanogaster. Human homologs have also been identified, but details of Notch function and interactions with its ligands are not well known in this context.

EGF-like domain

The EGF-like domain is an evolutionary conserved protein domain, which derives its name from the epidermal growth factor where it was first described. It comprises about 30 to 40 amino-acid residues and has been found in a large number of mostly animal proteins. Most occurrences of the EGF-like domain are found in the extracellular domain of membrane-bound proteins or in proteins known to be secreted. An exception to this is the prostaglandin-endoperoxide synthase. The EGF-like domain includes 6 cysteine residues which in the epidermal growth factor have been shown to form 3 disulfide bonds. The structures of 4-disulfide EGF-domains have been solved from the laminin and integrin proteins. The main structure of EGF-like domains is a two-stranded β-sheet followed by a loop to a short C-terminal, two-stranded β-sheet. These two β-sheets are usually denoted as the major (N-terminal) and minor (C-terminal) sheets. EGF-like domains frequently occur in numerous tandem copies in proteins: these repeats typically fold together to form a single, linear solenoid domain block as a functional unit.

Repeated sequences are patterns of nucleic acids that occur in multiple copies throughout the genome. Repetitive DNA was first detected because of its rapid re-association kinetics. In many organisms, a significant fraction of the genomic DNA is highly repetitive, with over two-thirds of the sequence consisting of repetitive elements in humans.

Function

Notch protein family members play a role in a variety of developmental processes by controlling cell fate decisions. The Notch signaling pathway is an evolutionarily conserved intercellular signaling pathway that regulates interactions between physically adjacent cells

Notch signaling pathway A series of molecular signals initiated by the binding of an extracellular ligand to the receptor Notch on the surface of a target cell, and ending with regulation of a downstream cellular process, e.g. transcription.

The Notch signaling pathway is a highly conserved cell signaling system present in most multicellular organisms. Mammals possess four different notch receptors, referred to as NOTCH1, NOTCH2, NOTCH3, and NOTCH4. The notch receptor is a single-pass transmembrane receptor protein. It is a hetero-oligomer composed of a large extracellular portion, which associates in a calcium-dependent, non-covalent interaction with a smaller piece of the notch protein composed of a short extracellular region, a single transmembrane-pass, and a small intracellular region.

In Drosophilia, notch interacts with its cell-bound ligands (delta and serrate), and establishes an intercellular signaling pathway that then plays a key role in development. Homologues of the notch-ligands have also been identified in humans, but precise interactions between these ligands and the human notch homologues remain to be determined. The notch protein is cleaved in the trans-Golgi network, and then presented on the cell surface as a heterodimer. The protein functions as a receptor for membrane bound ligands, and may play a role in vascular, renal, and hepatic development. [6]

Golgi apparatus A compound membranous cytoplasmic organelle of eukaryotic cells, consisting of flattened, ribosome-free vesicles arranged in a more or less regular stack. The Golgi apparatus differs from the endoplasmic reticulum in often having slightly thicker mem

The Golgi apparatus, also known as the Golgi complex, Golgi body, or simply the Golgi, is an organelle found in most eukaryotic cells. It was identified in 1897 by the Italian scientist Camillo Golgi and named after him in 1898.

Clinical significance

Mutations in the notch4 gene may be associated with susceptibility to schizophrenia in a small portion of cases. [7]

Schizophrenia Mental disorder characterized by abnormal behavior and misinterpretation of reality

Schizophrenia is a mental disorder characterized by abnormal behavior, strange speech, and a decreased ability to understand reality. Other symptoms include false beliefs, unclear or confused thinking, hearing voices that do not exist, reduced social engagement and emotional expression, and lack of motivation. People with schizophrenia often have additional mental health problems such as anxiety, depression, or substance-use disorders. Symptoms typically come on gradually, begin in young adulthood, and, in many cases, never resolve.

Related Research Articles

Notch 3 protein-coding gene in the species Homo sapiens

Neurogenic locus notch homolog protein 3 is a protein that in humans is encoded by the NOTCH3 gene.

JAG1 protein-coding gene in the species Homo sapiens

Jagged1 (JAG1) is one of five cell surface proteins (ligands) that interact with 4 receptors in the mammalian Notch signaling pathway. The Notch Signaling Pathway is a highly conserved pathway that functions to establish and regulate cell fate decisions in many organ systems. Once the JAG1-NOTCH (receptor-ligand) interactions take place, a cascade of proteolytic cleavages is triggered resulting in activation of the transcription for downstream target genes. Located on human chromosome 20, the JAG1 gene is expressed in multiple organ systems in the body and causes the autosomal dominant disorder Alagille syndrome (ALGS) resulting from loss of function mutations within the gene. JAG1 has also been designated as CD339.

Notch 1 protein-coding gene in the species Homo sapiens

Notch homolog 1, translocation-associated (Drosophila), also known as NOTCH1, is a human gene encoding a single-pass transmembrane receptor.

Ephrin B1 protein-coding gene in the species Homo sapiens

Ephrin-B1 is a protein that in humans is encoded by the EFNB1 gene.

WNT1 protein-coding gene in the species Homo sapiens

Proto-oncogene protein Wnt-1 is a protein that in humans is encoded by the WNT1 gene.

Notch 2 protein-coding gene in the species Homo sapiens

Neurogenic locus notch homolog protein 2 also known as notch 2 is a protein that in humans is encoded by the NOTCH2 gene.

ACP1 protein-coding gene in the species Homo sapiens

Low molecular weight phosphotyrosine protein phosphatase is an enzyme that in humans is encoded by the ACP1 gene.

FZD2 protein-coding gene in the species Homo sapiens

Frizzled-2 is a protein that in humans is encoded by the FZD2 gene.

FZD5 protein-coding gene in the species Homo sapiens

Frizzled-5 is a protein that in humans is encoded by the FZD5 gene.

FZD3 protein-coding gene in the species Homo sapiens

Frizzled-3 is a protein that in humans is encoded by the FZD3 gene.

TAAR6 protein-coding gene in the species Homo sapiens

Trace amine associated receptor 6, also known as TAAR6, is a protein which in humans is encoded by the TAAR6 gene.

CELSR1 protein-coding gene in the species Homo sapiens

Cadherin EGF LAG seven-pass G-type receptor 1 also known as flamingo homolog 2 or cadherin family member 9 is a protein that in humans is encoded by the CELSR1 gene.

Delta-like 1 protein-coding gene in the species Homo sapiens

Delta-like protein 1 is a protein that in humans is encoded by the DLL1 gene.

EPH receptor B4 protein-coding gene in the species Homo sapiens

Ephrin type-B receptor 4 is a protein that in humans is encoded by the EPHB4 gene.

Indian hedgehog (protein) protein-coding gene in the species Homo sapiens

Indian hedgehog homolog (Drosophila), also known as IHH, is a protein which in humans is encoded by the IHH gene. This cell signaling protein is in the hedgehog signaling pathway. The several mammalian variants of the Drosophila hedgehog gene have been named after the various species of hedgehog; the Indian hedgehog is honored by this one. The gene is not specific to Indian hedgehogs.

SLIT2 protein-coding gene in the species Homo sapiens

Slit homolog 2 protein is a protein that in humans is encoded by the SLIT2 gene.

Teratocarcinoma-derived growth factor 1 protein-coding gene in the species Homo sapiens

Teratocarcinoma-derived growth factor 1 is a protein that in humans is encoded by the TDGF1 gene. The protein is an extracellular, membrane-bound signaling protein that plays an essential role in embryonic development and tumor growth. Mutations in this gene are associated with forebrain defects. Pseudogenes of this gene are found on chromosomes 2, 3, 6, 8, 19 and X. Alternate splicing results in multiple transcript variants.

JAG2 protein-coding gene in the species Homo sapiens

Jagged-2 is a protein that in humans is encoded by the JAG2 gene.

DTX2 protein-coding gene in the species Homo sapiens

Protein deltex-2 also known as E3 ubiquitin-protein ligase DTX2 is an enzyme that in humans is encoded by the DTX2 gene.

KIR3DL3 protein-coding gene in the species Homo sapiens

Killer cell immunoglobulin-like receptor 3DL3 is a protein that in humans is encoded by the KIR3DL3 gene.

References

  1. 1 2 3 ENSG00000238196, ENSG00000204301, ENSG00000232339, ENSG00000223355, ENSG00000235396, ENSG00000206312 GRCh38: Ensembl release 89: ENSG00000234876, ENSG00000238196, ENSG00000204301, ENSG00000232339, ENSG00000223355, ENSG00000235396, ENSG00000206312 - Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000015468 - Ensembl, May 2017
  3. ↑ "Human PubMed Reference:".
  4. ↑ "Mouse PubMed Reference:".
  5. ↑ Sugaya K, Fukagawa T, Matsumoto K, Mita K, Takahashi E, Ando A, Inoko H, Ikemura T (Feb 1995). "Three genes in the human MHC class III region near the junction with the class II: gene for receptor of advanced glycosylation end products, PBX2 homeobox gene and a notch homolog, human counterpart of mouse mammary tumor gene int-3". Genomics. 23 (2): 408–19. doi:10.1006/geno.1994.1517. PMID   7835890.
  6. 1 2 "Entrez Gene: NOTCH4 Notch homolog 4 (Drosophila)".
  7. ↑ Shayevitz C, Cohen OS, Faraone SV, Glatt SJ (July 2012). "A re-review of the association between the NOTCH4 locus and schizophrenia". Am. J. Med. Genet. B Neuropsychiatr. Genet. 159B (5): 477–83. doi:10.1002/ajmg.b.32050. PMID   22488909.

Further reading


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