Nuclear-interacting partner of ALK (NIPA), also known as zinc finger C3HC-type protein 1 (ZC3HC1), is a

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...

that in humans is encoded by the ''ZC3HC1''

gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...

chromosome 7 Chromosome 7 is one of the 23 pairs of chromosomes in humans, who normally have two copies of this chromosome. Chromosome 7 spans about 160 million base pairs (the building material of DNA) and represents between 5 and 5.5 percent of the total DN ...

. It is ubiquitously expressed in many tissues and cell types though exclusively expressed in the

nuclear Nuclear may refer to: Physics Relating to the nucleus of the atom: *Nuclear engineering *Nuclear physics *Nuclear power *Nuclear reactor *Nuclear weapon *Nuclear medicine *Radiation therapy *Nuclear warfare Mathematics * Nuclear space *Nuclear ...

subcellular location. NIPA is a skp1

cullin Cullins are a family of hydrophobic scaffold proteins which provide support for ubiquitin ligases (E3). All eukaryotes appear to have cullins. They combine with RING proteins to form ''Cullin-RING ubiquitin ligases'' (CRLs) that are highly div ...

F-box (SCF)-type ubiquitin E3 ligase (SCFNIPA) complex protein involved in regulating entry into

mitosis Mitosis () is a part of the cell cycle in eukaryote, eukaryotic cells in which replicated chromosomes are separated into two new Cell nucleus, nuclei. Cell division by mitosis is an equational division which gives rise to genetically identic ...

. The ''ZC3HC1'' gene also contains one of 27

SNPs In genetics and bioinformatics, a single-nucleotide polymorphism (SNP ; plural SNPs ) is a germline substitution of a single nucleotide at a specific position in the genome. Although certain definitions require the substitution to be present in ...

associated with increased risk of

coronary artery disease Coronary artery disease (CAD), also called coronary heart disease (CHD), or ischemic heart disease (IHD), is a type of cardiovascular disease, heart disease involving Ischemia, the reduction of blood flow to the cardiac muscle due to a build-up ...

Structure

Gene

The ''ZC3HC1'' gene resides on chromosome 7 at the band 7q32.2 and includes 14

exon An exon is any part of a gene that will form a part of the final mature RNA produced by that gene after introns have been removed by RNA splicing. The term ''exon'' refers to both the DNA sequence within a gene and to the corresponding sequence ...

Protein

NIPA is a 60-kDa E3 ligase that contains one C3HC-type

zinc finger A zinc finger is a small protein structural motif that is characterized by the coordination of one or more zinc ions (Zn2+) which stabilizes the fold. The term ''zinc finger'' was originally coined to describe the finger-like appearance of a ...

and one F-box-like region. Moreover, a 50- residue region (amino acids 352-402) at its

C-terminal The C-terminus (also known as the carboxyl-terminus, carboxy-terminus, C-terminal tail, carboxy tail, C-terminal end, or COOH-terminus) is the end of an amino acid chain (protein or polypeptide), terminated by a free carboxyl group (-COOH). When t ...

serves as the nuclear translocation signal (NLS sequence) while a 96-residue region (amino acids 306-402) is proposed to serve as the

phosphotyrosine-binding domain In molecular biology, phosphotyrosine-binding domains are protein domains which bind to phosphotyrosine. The phosphotyrosine-binding domain (PTB, also phosphotyrosine-interaction or PI domain) in the protein tensin tends to be found at the C- ...

. NIPA is one component of the nuclear SCFNIPA complex, and phosphorylation of NIPA at three serine residues, Ser-354, Ser-359 and Ser-395, has been demonstrated to inactivate the complex as a whole.

Function

NIPA is broadly expressed in the human tissues, with the highest expression in heart, skeletal muscle, and testis. It is a human F-box protein that defines an SCF-type

ubiquitin Ubiquitin is a small (8.6 kDa) regulatory protein found in most tissues of eukaryotic organisms, i.e., it is found ''ubiquitously''. It was discovered in 1975 by Gideon Goldstein and further characterized throughout the late 1970s and 19 ...

E3 ligase, the formation of which is regulated by cell-cycle-dependent phosphorylation of NIPA.

Cyclin B1 G2/mitotic-specific cyclin-B1 is a protein that in humans is encoded by the ''CCNB1'' gene. Function Cyclin B1 is a regulatory protein involved in mitosis. The gene product complexes with p34 (Cdk1) to form the maturation-promoting factor (MP ...

, essential in the entry into

, is targeted by SCFNIPA in interphase. Phosphorylation of NIPA occurs in

G2 phase G2 phase, Gap 2 phase, or Growth 2 phase, is the third subphase of interphase in the cell cycle directly preceding mitosis. It follows the successful completion of S phase, during which the cell’s DNA is replicated. G2 phase ends with the o ...

, results in dissociation of NIPA from the SCF core, and has been proven critical for proper G2/M transition. Oscillating

ubiquitination Ubiquitin is a small (8.6 kDa) regulatory protein found in most tissues of eukaryotic organisms, i.e., it is found ''ubiquitously''. It was discovered in 1975 by Gideon Goldstein and further characterized throughout the late 1970s and 19 ...

of nuclear cyclin B1 driven by the SCFNIPA complex contributes to the timing of mitotic entry. NIPA is also reported to delay

apoptosis Apoptosis (from ) is a form of programmed cell death that occurs in multicellular organisms and in some eukaryotic, single-celled microorganisms such as yeast. Biochemistry, Biochemical events lead to characteristic cell changes (Morphology (biol ...

and the localization of NIPA is required for this antiapoptotic function.

Clinical relevance

In humans, NIPA has been implicated in cardiovascular diseases by genome-wide association (GWAS) studies. Specifically, a

single-nucleotide polymorphism In genetics and bioinformatics, a single-nucleotide polymorphism (SNP ; plural SNPs ) is a germline substitution of a single nucleotide at a specific position in the genome. Although certain definitions require the substitution to be present in a ...

(SNP) situated in ZC3HC1 has been shown to predict coronary artery disease. This prediction appears to be independent of traditional risk factors for cardiovascular disease such as high cholesterol levels, high blood pressure, obesity, smoking and diabetes mellitus, which are primary targets of current treatments for coronary artery disease. Therefore, studying the function of this gene may identify novel pathways contributing to coronary artery disease that result in the development of novel therapeutics.

Clinical marker

At the coronary artery disease-associated locus 7q32.2, only a single SNP (rs11556924) is associated with coronary artery disease risk, with no other variants in strong linkage disequilibrium. The rs11556924 SNP in the ZC3HC1 gene results in an arginine-histidine polymorphism at amino acid residue 363 in NIPA. Furthermore, rs11556924 has also been associated with altered carotid intima-media thickness in patients with rheumatoid arthritis and with altered risk of atrial fibrillation. Additionally, a multi-locus genetic risk score study based on a combination of 27 loci, including the ZC3HC1 gene, identified individuals at increased risk for both incident and recurrent coronary artery disease events, as well as an enhanced clinical benefit from statin therapy. The study was based on a community cohort study (the Malmo Diet and Cancer study) and four additional randomized controlled trials of primary prevention cohorts (JUPITER and ASCOT) and secondary prevention cohorts (CARE and PROVE IT-TIMI 22).