COMMD1 gene

COMMD1 location:

     COMMD 1 gene lies on chromosome 2.Its location is 2p15.

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The designation of homologs of MURR1 identified here required the generation of a new nomenclature. Murr1 derived its name from its proximity to the U2af1-rs1 locus in mice (mouse U2af1-rs1 region 1); however, this genomic organization is not observed in other organisms including humans. In addition, an unrelated gene that also lies in close proximity to U2af1-rs1 has been designated Murr2, precluding the use of this name for MURR1 homologs .In consultation with the HUGO gene nomenclature committee, the term COMMD (COMM Domain containing) is proposed to designate these factors based on the shared structural domain that defines this family of proteins and has been adopted in NCBI public databases. The name COMMD1 is suggested for MURR1 as a means to standardize the nomenclature to designate this protein family and will be used hereafter

Genomic location: bands according to Ensembl, locations according to Geneloc)

Gene Loc location for GC02P062044:     (about GC identifiers)

Start:            61,986,292 bp from pter

End:             62,216,709 bp from pter

Size:             230,417 bases

Exon structure:

   From Entrez Gene:
Id
Chromosome
Contig
Strand
Exon Start
Exon End
150684
2

+
61986307
61986317
150684
2

+
61986318
61986497
150684
2

+
62081340
62081621
150684
2

+
62216470
62216580
150684
2

+
62216581
62216709

   From Ensemble:
Id
Chromosome
Contig
Strand
Exon Start
Exon End
ENSG00000173163
2

+
61986292
61986497
ENSG00000173163
2

+
62081340
62081621
ENSG00000173163
2

+
62216470
62216698

     The structure N-commd1 has a ? helical fold with little resemblance to other ? helical  proteins .The compact nature of N-COMMD1 suggests that full length proteins are modular with a precise function for each domain. Several areas are positively charged which provide an area for interaction with other negatively charged areas in COMMD proteins. (Sommerhalter. Zhang. Rosenweig.2007)

     COMMD1 RNA is expressed in the liver as well as many other tissues. COMMD1 contains no copper binding motifs but it does contain the COMM domain. The COMM domain is leucine rich and has approximately 85 amino acids. (Klomp, Van De Sluis. Wijmenga. Di Bie, 2005) this domain is present in 9 other human genes COMMD 2-10. All Commd proteins have been found to complex with COMMD 1 although the exact structure of these complexes in vivo needs to be determined. The exact molecular function of COMMD1 remains unknown however it is seen in a number of cellular processes.

COMMD-COMMD interactions. Each of the 10 COMMD proteins was expressed in 293 cells in fusion with GST and precipitated (IP) from cell lysates by glutathione-Sepharose beads. The presence of endogenous COMMD1 in the precipitates was determined by immunoblotting. B, schematic representation of COMMD1 and the amino acid residues that are the boundaries for interaction mapping experiments. C and D, the COMM domain is required for the association of COMMD proteins. COMMD1-Flag (C) or COMMD3-FLAG (D) were expressed in 293 cells along with various regions of COMMD1 in fusion with GST as indicated. COMMD1-GST was precipitated from cell lysates by glutathione-Sepharose beads and the presence of COMMD1 or -3 in the precipitates was determined by immunoblotting (WB) with a Flag antibody.(Burstein, E. Hoberg, J. Wilkinson, A. Rumble, J. Csomos, R. Komarck ,C. Maine ,G. Wilkinson, J. Mayo, M and Duckett, C. 2005)

COMMD 1 promoters and terminators.

     The promoter and terminator genes have yet to be identified. COMMD1 levels are regulated by an x linked inhibitor of apoptosis (XIAP).This is an E3 ubitiquin ligase that targets COMMD1 for proteasomal degradation. (Burstien et al.2004) a number of proteins involved in copper homeostasis or requiring copper for their function are regulated at their protein levels in response to copper levels. These are hephaestin, Cu/Zn superoxide dismutase and the copper transporter CTR1.It remains to be investigated if copper levels regulate XIAP activity. . (Klomp, Van De Sluis. Wijmenga. Di Bie,2005) It has been seen that COMMD1 levels remain constant under changing copper levels showing that copper regulation of XIAP maybe unlikely.

     Unlike other nuclease regulators of ?? such as histone acetylates and deacetylases the COMMD proteins possess no apparent intrinsic enzymatic activity. The transcriptional inhibitory function of COMMD must be regulated in turn by stimuli possibly post translational modifications. XIAP a stress responsive prosurvival factor can break down COMMD1 suggesting that the regulation of COMMD proteins might be integrated into cellular responses that are known to activate NF-??. (Burstin. Hoberg.Wilkinson.Rumble.Csomos.Maine.Mayo.2007)

Interactions with other COMMD proteins:

     COMMD1 can interact with all other COMMD proteins. The carboxyl terminus of COMMD1 (exon 2-3) which contains the Comm domain was found sufficient for interactions with COMMD1 and COMMD3 .The lack of COMMD1 in exon 1- GST fusion protein inhibits protein binding. So the COMM domain in this family of proteins in necessary for COMMD –COMMD interactions.

     Several COMMD proteins suppress ?? mediated transcription. COMMD 1, 2, 4, 7, 9 and 10 were strongly able to inhibit TNF mediated NF-?? activation and COMMD3 and 8 weakly inhibited.

     COMMD proteins can associate with NF-?? subunits but differences are present. COMMD1 can associate with all five subunits and is the only COMMD able to precipitate c-Rel whereas COMMD 2 associated with NF-?? subunits but bound more strongly to Rel-B containing subunits.

     COMMD-COMMD interactions seem to require only the COMM domain but COMMD-RelA seem to require the presence of more then just the COMM domain

. COMMD6 is predicted to be a ubiquitously expressed small (8 kDa) soluble protein, which could potentially function as a homomultimer. COMMD6 sequences appear to be highly conserved during evolution, although, in humans, a COMMD6 splice variant is expressed that has not been observed in other organisms, and the predicted N-termini of COMMD6 proteins in higher organisms are significantly smaller than those observed in lower organisms. In fact, COMMD6 in higher vertebrates consists primarily of the COMM domain, indicating that the COMMD is important, and maybe even sufficient, for CO MMD6 function. The interaction between COMMD1 and COMMD6 was abolished by deletion of exon 3 of COMMD1. This confirms independently that interaction between COMMD proteins is mediated by the COMM domain, and that the C-terminal part of the COMM domain could be sufficient for interaction (De Bie, P. Van de Sluis, B. Burstein, E. Duran, K. Berger, R. Duckett, C. Wijmenga, C.Klomp, and L.2006.)

Gene Function

MURRI protein (COMMD1) has several relevant functions including

Regulates signalling of a nuclear factor kappa –B (NF-kB) which is responsible for Apoptosis, Cell cycle regulation, Oncogensis and adaptive immunity.
Regulates copper homeostasis
Regulates sodium uptake

MURR1 is multitasking and multifunctional protein. One of the most important functions associated with this family that it inhibits nuclear factor -?B (NF-?B).

Inhibition of NF-kB

     Nuclear Factor Kappa B (NF-kB) is formed with a different kind of proteins family conserved for a specific Rel Homology domain (RHD). It is dimeric complex involved in various transcriptional processes. Its main function is to regulate transcription process at various levels of genetic coding. As all bodily functions are controlled by genetic codes and commands, hence, Nf-kB factor is almost involved in unlimited number of biological processes. These include varied number of bodily processes including cell death, cell’s life cycle, immune responses, apoptosis, regeneration, cytoplasm sequestration, transcription of viral genomes, viral cycle progression and other cell processes. NF-kB is most condensed in region of cytoplasm thought interactions with complexes of the I?? family. I?? proteins act as inhibitors by binding to NF-?? and masking them .I?? contain ankyrin repeats which allows their interaction with NF-?? and masks them. Phosphorylation of I?? proteins by kinases results in NF-?? being unmasked and nuclear translocation and transcription of ?? target genes.

     It is thought that COMMD1 protects the breakdown of I?? by proteases in the cytoplasm and so prevents NF-?? from exerting its effects in the nucleus.

Another possibility of the role of COMMD1 in this regulation of NF-?? has been postulated with COMMD1 preventing interaction of NF-?? at its promoter site in the nucleus. COMMD1 interacts with NF-?? promoter site and prevents NF-?? from binding at this site.

     In addition COMMD1 was found to affect ??- responsive transcription factors

from viral and endogenous promoters including HIV-enhancer. It can act as a factor

that limits HIV replication in resting CD4 lymphocytes.

COMMD1 and both isoforms of COMMD6 inhibited NF-?B to a similar extent

Co-expression of both COMMD1 and COMMD6 did not exacerbate the

inhibition of NF-?B-mediated transcription, suggesting that both proteins exert

their effect through the same pathway. Consistent with this observation, both

COMMD1 and COMMD6 are associated with the RelA subunit of NF-?B.

Previously, it has been suggested that COMMD1 regulates the proteasomal

degradation of I?B? but, whereas COMMD1 is associated with I?B?, no

binding of COMMD6 to I?B? was observed. The most straightforward

explanation of these data is that the COMM domain of COMMD1 acts to

recruit COMMD6 to the NF-?B complex after TNF-induced dissociation of

I?B?. This would eventually result in inhibition of NF-?B-mediated

transcriptional activation. (De Bie, P. Van de Sluis, B. Burstein, E.Duran, K. Berger,

R.Duckett, C.Wijmenga, C.Klomp, L.2006.)

     Once activated, NF- B can mediate expression of multiple gene targets. However, the observed responses are often specific to the cell type and stimulus in question. For example, NF- B has been reported to be able to activate transcription of both pro- and anti-apoptotic factors in various settings. The regulation of NF- B solely by I B-mediated sequestration of the complex is unlikely to account for these differences in gene expression. In this regard, post-translational modifications of NF- B and preferential promoter binding by different subunits have been shown to participate in the regulation of certain promoters in response to specific stimuli .However, additional layers of regulation that could account for the tissue- and promoter-specific nature of the response are likely at play. The identification here of the COMMD family reveals an additional regulatory level that might be important in this regard. The conservation of all 10 COMMD genes through vertebrate evolution and the differential pattern of association to NF- B complexes suggest that despite their similarities, COMMD proteins probably serve unique and non-redundant functions. A thorough understanding of the mode of action of these factors in different cell types may help to account for the precision and selectivity by which expression of the multitude of NF- B-responsive genes can be orchestrated in response to a diverse range of stimuli. (Burstein, E. Hoberg, J. Wilkinson, A. Rumble, J. Csomos, R. Komarck , C. Maine ,G. Wilkinson, J. Mayo, M and Duckett, C.2005)

Na+ homeostasis via regulation of human gamma epithelial sodium channels

     Murr1 (mouse U2af1-rs1 region) is involved in regulation of human gamma epithelial sodium channels (gENaC) (Wolfgang et al 2003). These channel control flow of Na+ into the blood hence play vital role in homeostasis of Na+ in body. Na+ is very important mineral required in body with and tightly regulated. Any kind of minute deregulation can cause unbalanced distribution of Na+ in the body. Maintenance of Na+ normal amount in blood is very important fact in various physiological processes.

     ENaC is very important sodium channel present at various locations of apical membranes in the body. Most abundant of these ion channels are present at the polarized epithelial cells of apical membrane present in kidney, lungs and colon. It is mostly involved in the regulation of Na+ uptake and homeostasis of Na+ and K+ ions in the body. It maintains normal balance of Na+/K+ ions in the blood and extra-cellular fluids. It is mostly regulated by mineral corticoid aldosterone. It is also present in taste receptor cells. Salt taste is perceived because of its important role in perception. All subunits jointly make the channels functional.

.

ENaC

     Aldosterone is involved in regulation of these Na+ channels. ENaC is regulated with gene expression. Serum- and glucocorticoid-inducible kinase-1 [SGK1] regulates the expression of gene for ENaC. SGK1 plays vital role in its regulation. Any kind of disease that causes in ability of SGK1 can reduce the gene expression of Beta and gamma subunits of the channel. Transcriptional factor mediate transcription of ENaC.

     Enac is made up of three subunits ?, ? and ?. An additional subunit delta has been reported to cooperate with ? and ? units to create an amiloride induced sodium current. COMMD1 has been seen to complex with ?, ? and ? and a complex of these is seen to inhibit the amiloride induced sodium current. ATP7b has also seen to interact with COMMD1 in this process. . (Klomp, Van De Sluis. Wijmenga. Di Bie, 2005)

Gene Regulatory Role in Copper Homeostasis

     Copper homeostasis is one of the most important functions regulated by these genes. Copper is a trace element and required as a cofactor for a number of enzymes in the body such as copper /zinc superoxide dismutase and cytochrome c. Superoxide dismutase protects the cell from free radicals while cytochrome c takes part in the mitochondrial respiratory chain. Copper exists in two oxidation states and this makes it toxic if in excess as it can create reactive oxygen species like superoxide. The constant regulation of copper is the basis of many important physiological functions. Any imbalance in copper regulation can cause disruption in normal physiological functions. Copper is very important co-factor used in many important metabolic reactions of the body. It is required in a specific amount by the body to accomplish important biochemical reactions. Abundance and depletion of copper can cause varied kind of malfunctioning and diseases. Copper is excreted by the liver through the bile… COMMD1 involvement in various functions has been suggested like ion transport and trafficking of vesicles. The enzyme ATP7B plays a vital role in its proper transport and regulation. It is a p type copper translocating enzyme that is structurally and functionally homologous to ATP7A.

     On entering the cell through a copper transporter CTR1 copper is delivered to the Golgi by ATOX1 a copper carrier. ATOX 1 binds to copper and undergoes a transient association with ATP7b. ATP7b is normally in the Golgi but when copper levels in the cell are elevated it is found in vesicles as well. ATP7a is also similarly in the Golgi and when copper levels are raised it is seen in the vesicles. Copper in these vesicles is excreted from the cell in an unknown manner.

COMMD1 can bind to the N-terminal region of ATP7b but not ATP7a. It has been suggested that this interaction is responsible for the excretion of copper from liver cells.

     Any disease affecting gene of ATP7B gene can alter this function and result in a disease called Wilson’s disease. It has been suggested that this protein COMMD1 is involved in interaction with the N-terminal domain of ATP7B gene in Wilson’s disease (Tao et al. (23). ATOX1 has also been implicated

     .Copper toxicosis and Wilson’s disease are due to genetic defects in certain genes. Defective gene of Wilson’s disease lies on the chromosome 13. In normal healthy individuals this gene codes for ATP7B. This P-type of ATPase is mostly responsible for copper transport. Due to defective gene regulation copper’s normal storage is disrupted. Liver cirrhosis is the ultimate result of this. MURR1 genes have been identified to be defective in this disease.

Wilson’s disease (Copper abundance)

     One of the inherited disorders of copper metabolism that results from defect in autosomal recessive gene. Improper break down of copper results in excessive accumulation in cornea of the eye, brain and liver causing extensive hepatic and neurological abnormalities.

Menkes Disease (Copper deficiency)

     It is due to a deficiency of copper causes by a failure to malbsorption of copper. It results in retardation of growth, Kinky hair, focal cerebral and cerebellar degeneration. IT is caused by a mutation in ATP7A gene.

Copper toxicosis in dogs:

     COMMD1 was implicated as a regulator of copper metabolism by the discovery that a deletion of exon 2 of COMMD1 causes copper toxicosis in Bedlington terriers.

A deletion in the copper metabolism (Murr1) domain containing 1 (COMMD1) gene is associated with hepatic copper toxicosis in dogs. In a dog hepatic cell line, we analyzed the copper metabolic functions after an 80% (mRNA and protein) COMMD1 reduction with COMMD1-targeting siRNAs. Exposure to 64Cu resulted in a significant increase in copper retention in COMMD1-depleted cells. COMMD1-depleted cells were almost three times more sensitive to high extracellular copper concentrations. Copper-mediated regulation of metallothionein gene expression was enhanced in COMMD1-depleted cells. (B. Spee, B. Arends, A. M. T. C. van Wees, P. Bode, L. C. Penning, J. Rothuizen 2007)

REFERNCES:

       Biasco, W. Chang, T. McIntosh, J. Mcdonalds, F .Identification of MURR1 as regulator of human delta epithelial sodium channel. (2004) the Journal of Biochemistry.Vol279.No.7.5429-5434. American Society for Biochemistry and molecular biology.

       Burstein, E. Hoberg, J. Wilkinson, A. Rumble, J. Csomos, R. Komarck ,C. Maine ,G. Wilkinson, J. Mayo, M and Duckett, C. (2005) COMMD Proteins, a Novel Family of Structural and Functional Homologs of MURR1. J. Biol. Chem., Vol. 280, Issue 23

Retrieved from the World Wide Web from http://www.jbc.org/cgi/content/full/280/23/22222#FIG3 on the 7th of May 2007.

     De Bie, P. Van De Sluis, B. Klomp and L.Wijmenga, C (2005) The many faces of Copper metabolism Protein COMMD1/ MURR1. Journal of heredity. American Genetics association.

     De Bie,P. Van de Sluis, B. Burstein, E. Duran, K. Berger, R. Duckett, C. Wijmenga ,C. Klomp, L(2006)Characterization of COMMD protein–protein interactions in NF-?B signalling Biochemistry journal 2006. The Biochemical society, London.

Retrieved from the world wide web on the 7th of may 2007 from:

http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1525016

     Sommerhalter, M. Zhang, Y. Rosenweig, A. solution Structure of COMMD1 N-terminal domain. (2007) Journal of Molecular Biology.715-721.Elsevier.

      Spee, B. Arends, A. M. T. C. van Wees, P. Bode, L. C. Penning, J. Rothuizen (2007) Functional consequences of RNA interference targeting COMMD1 in a canine hepatic cell line in relation to copper toxicosis
Animal Genetics 38 (2), 168–170.

 

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