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SMC4
Protein-coding gene in the species Homo sapiens

Structural maintenance of chromosomes protein 4 (SMC-4) also known as chromosome-associated polypeptide C (CAP-C) or XCAP-C homolog is a protein that in humans is encoded by the SMC4 gene. SMC-4 is a core subunit of condensin I and II, large protein complexes involved in high order chromosome organization, including condensation and segregation. SMC-4 protein is commonly associated with the SMC-2 protein, another protein complex within the SMC protein family. SMC-4 dimerizes with SMC-2, creating the flexible and dynamic structure of the condensin holocomplex. An over-expression of the SMC-4 protein is shown to impact carcinogenesis.

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Structure and interactions

The primary 5 domain structure of SMC proteins is highly conserved among species. The basic structure of SMC proteins are characterized by a non-helical hinge group, separated by two anti-parallel α-helical coiled-coil domains, along with two Amino-terminal globular domains containing ATP hydrolytic sites, or nucleotide-binding motifs located at the C-terminus and N-terminus called the Walker A and Walker B motifs.10

In eukaryotes, dimerization is mediated by the self-folding of the non-helical hinge group on the SMC protein. Dimerization occurs at the non-helical hinge group of SMC-4, which then associates with the non-helical hinge group of SMC-2, creating a V-shaped heterodimeric structure. the holocomplex of condensin contains the SMC-4 and SMC-2 heterodimer subunits, along with 3 other non-SMC subunits, CAP-D2, CAP-G, and CAP-H.11

In the condensin holocomplex, a protein subunit called kleisin joins the C-terminus and N-terminus ATPase end domains of both SMC-4 and SMC-2 proteins. when the condensin holocomplex is bound with ATP at these end domains, the condensin will assume a "closed" conformation state.12 SMC-4 is a dynamic and flexible protein, allowing different domain components to occasionally interact with others. This is speculated to be involved in the mechanical ability of the complex when associated with chromosomes.13 In budding yeast, these interactions may result in open "O" appearances, or collapsed B-shaped states as a result of its dynamic ability.14

Clinical significance

The SMC-4 protein is associated with abnormal cell and tumor growth, and involved with migration and invasion. In general, the presence of over-expressed SMC-4 proteins is thought to be correlated with carcinogenesis.15

It is found that an over-expression or down-regulation of the SMC-4 protein alters TGFβ/Smad signaling pathways in glioma cells. SMC-4-transduced glioma cells showed activation of the TGFβ/Smad signaling pathway which was not present in SMC-4 silenced glioma cells. This pathway was shown to be correlated with an "aggressive" behavioral phenotype in glioma cells. An over-expression of SMC-4 can induce a higher rate of proliferation, and ultimately increased invasive capability. A down-regulation of SMC-4 reduced this quality.16

The SMC-4 protein is involved with normal lung development however, adenocarcinoma lung tissue shows an over-expression of SMC-4. additionally, SMC-4 may act as independent prognostic factor for carcinogenesis and lung adenocarcinoma.17

Studies suggest that over-expression of the SMC-4 protein in human liver tissue may be correlated with progression of hepatocellular carcinoma.18

Further reading

  • SMC4 human gene location in the UCSC Genome Browser.
  • SMC4 human gene details in the UCSC Genome Browser.
  • PDBe-KB provides an overview of all the structure information available in the PDB for Human Structural maintenance of chromosomes protein 4 (SMC4)
  • PDBe-KB provides an overview of all the structure information available in the PDB for Mouse Structural maintenance of chromosomes protein 4 (SMC4)

References

  1. "Entrez Gene: SMC4 structural maintenance of chromosomes 4". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=10051 ↩

  2. Nishiwaki T, Daigo Y, Kawasoe T, Nagasawa Y, Ishiguro H, Fujita M, et al. (Jun 1999). "Isolation and characterization of a human cDNA homologous to the Xenopus laevis XCAP-C gene belonging to the structural maintenance of chromosomes (SMC) family". Journal of Human Genetics. 44 (3): 197–202. doi:10.1007/s100380050142. PMID 10319587. https://doi.org/10.1007%2Fs100380050142 ↩

  3. Schmiesing JA, Ball AR, Gregson HC, Alderton JM, Zhou S, Yokomori K (October 1998). "Identification of two distinct human SMC protein complexes involved in mitotic chromosome dynamics". Proceedings of the National Academy of Sciences of the United States of America. 95 (22): 12906–12911. Bibcode:1998PNAS...9512906S. doi:10.1073/pnas.95.22.12906. PMC 23650. PMID 9789013. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC23650 ↩

  4. Eeftens JM, Katan AJ, Kschonsak M, Hassler M, de Wilde L, Dief EM, et al. (March 2016). "Condensin Smc2-Smc4 Dimers Are Flexible and Dynamic". Cell Reports. 14 (8): 1813–1818. doi:10.1016/j.celrep.2016.01.063. PMC 4785793. PMID 26904946. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4785793 ↩

  5. Zhang C, Kuang M, Li M, Feng L, Zhang K, Cheng S (September 2016). "SMC4, which is essentially involved in lung development, is associated with lung adenocarcinoma progression". Scientific Reports. 6 (1): 34508. Bibcode:2016NatSR...634508Z. doi:10.1038/srep34508. PMC 5043270. PMID 27687868. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5043270 ↩

  6. Eeftens JM, Katan AJ, Kschonsak M, Hassler M, de Wilde L, Dief EM, et al. (March 2016). "Condensin Smc2-Smc4 Dimers Are Flexible and Dynamic". Cell Reports. 14 (8): 1813–1818. doi:10.1016/j.celrep.2016.01.063. PMC 4785793. PMID 26904946. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4785793 ↩

  7. Jiang L, Zhou J, Zhong D, Zhou Y, Zhang W, Wu W, et al. (March 2017). "Overexpression of SMC4 activates TGFβ/Smad signaling and promotes aggressive phenotype in glioma cells". Oncogenesis. 6 (3): e301. doi:10.1038/oncsis.2017.8. PMC 5533949. PMID 28287612. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5533949 ↩

  8. Zhou B, Chen H, Wei D, Kuang Y, Zhao X, Li G, et al. (June 2014). "A novel miR-219-SMC4-JAK2/Stat3 regulatory pathway in human hepatocellular carcinoma". Journal of Experimental & Clinical Cancer Research. 33 (1): 55. doi:10.1186/1756-9966-33-55. PMC 4096530. PMID 24980149. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4096530 ↩

  9. Zhang C, Kuang M, Li M, Feng L, Zhang K, Cheng S (September 2016). "SMC4, which is essentially involved in lung development, is associated with lung adenocarcinoma progression". Scientific Reports. 6 (1): 34508. Bibcode:2016NatSR...634508Z. doi:10.1038/srep34508. PMC 5043270. PMID 27687868. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5043270 ↩

  10. Hirano T (February 2002). "The ABCs of SMC proteins: two-armed ATPases for chromosome condensation, cohesion, and repair". Genes & Development. 16 (4): 399–414. doi:10.1101/gad.955102. PMID 11850403. S2CID 45664625. https://doi.org/10.1101%2Fgad.955102 ↩

  11. Zhang C, Kuang M, Li M, Feng L, Zhang K, Cheng S (September 2016). "SMC4, which is essentially involved in lung development, is associated with lung adenocarcinoma progression". Scientific Reports. 6 (1): 34508. Bibcode:2016NatSR...634508Z. doi:10.1038/srep34508. PMC 5043270. PMID 27687868. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5043270 ↩

  12. Eeftens JM, Katan AJ, Kschonsak M, Hassler M, de Wilde L, Dief EM, et al. (March 2016). "Condensin Smc2-Smc4 Dimers Are Flexible and Dynamic". Cell Reports. 14 (8): 1813–1818. doi:10.1016/j.celrep.2016.01.063. PMC 4785793. PMID 26904946. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4785793 ↩

  13. Eeftens JM, Katan AJ, Kschonsak M, Hassler M, de Wilde L, Dief EM, et al. (March 2016). "Condensin Smc2-Smc4 Dimers Are Flexible and Dynamic". Cell Reports. 14 (8): 1813–1818. doi:10.1016/j.celrep.2016.01.063. PMC 4785793. PMID 26904946. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4785793 ↩

  14. Ryu JK, Katan AJ, van der Sluis EO, Wisse T, de Groot R, Haering CH, Dekker C (December 2020). "The condensin holocomplex cycles dynamically between open and collapsed states". Nature Structural & Molecular Biology. 27 (12): 1134–1141. doi:10.1038/s41594-020-0508-3. PMID 32989304. S2CID 222146992. /wiki/Doi_(identifier) ↩

  15. Jiang L, Zhou J, Zhong D, Zhou Y, Zhang W, Wu W, et al. (March 2017). "Overexpression of SMC4 activates TGFβ/Smad signaling and promotes aggressive phenotype in glioma cells". Oncogenesis. 6 (3): e301. doi:10.1038/oncsis.2017.8. PMC 5533949. PMID 28287612. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5533949 ↩

  16. Jiang L, Zhou J, Zhong D, Zhou Y, Zhang W, Wu W, et al. (March 2017). "Overexpression of SMC4 activates TGFβ/Smad signaling and promotes aggressive phenotype in glioma cells". Oncogenesis. 6 (3): e301. doi:10.1038/oncsis.2017.8. PMC 5533949. PMID 28287612. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5533949 ↩

  17. Zhang C, Kuang M, Li M, Feng L, Zhang K, Cheng S (September 2016). "SMC4, which is essentially involved in lung development, is associated with lung adenocarcinoma progression". Scientific Reports. 6 (1): 34508. Bibcode:2016NatSR...634508Z. doi:10.1038/srep34508. PMC 5043270. PMID 27687868. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5043270 ↩

  18. Zhou B, Chen H, Wei D, Kuang Y, Zhao X, Li G, et al. (June 2014). "A novel miR-219-SMC4-JAK2/Stat3 regulatory pathway in human hepatocellular carcinoma". Journal of Experimental & Clinical Cancer Research. 33 (1): 55. doi:10.1186/1756-9966-33-55. PMC 4096530. PMID 24980149. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4096530 ↩